FORM 4 [ ] Check this box if no longer subject to Section 16. Form 4 or Form 5 obligations may continue. See Instruction 1(b).         
UNITED STATES SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
STATEMENT OF CHANGES IN BENEFICIAL OWNERSHIP OF SECURITIES
                                                                                  
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Filed pursuant to Section 16(a) of the Securities Exchange Act of 1934 or Section 30(h) of the Investment Company Act of 1940
                      
1. Name and Address of Reporting Person * BERTHELSEN SPENCER R 2. Issuer Name and Ticker or Trading Symbol IONIS PHARMACEUTICALS INC [ IONS ] 5. Relationship of Reporting Person(s) to Issuer (Check all applicable)__X__ Director                    _____ 10% Owner
_____ Officer (give title below)    _____ Other (specify below)
(Last)         (First)         (Middle)
2855 GAZELLE COURT
3. Date of Earliest Transaction (MM/DD/YYYY)
6/23/2021
(Street)
CARLSBAD, CA 92010
(City)       (State)       (Zip)
4. If Amendment, Date Original Filed (MM/DD/YYYY)
 
6. Individual or Joint/Group Filing (Check Applicable Line) _X _ Form filed by One Reporting Person
___ Form filed by More than One Reporting Person

Table I - Non-Derivative Securities Acquired, Disposed of, or Beneficially Owned
1.Title of Security
(Instr. 3)
2. Trans. Date 2A. Deemed Execution Date, if any 3. Trans. Code
(Instr. 8)
4. Securities Acquired (A) or Disposed of (D)
(Instr. 3, 4 and 5)
5. Amount of Securities Beneficially Owned Following Reported Transaction(s)
(Instr. 3 and 4)
6. Ownership Form: Direct (D) or Indirect (I) (Instr. 4) 7. Nature of Indirect Beneficial Ownership (Instr. 4)
Code V Amount (A) or (D) Price
Common Stock  6/23/2021  6/23/2021  M    15000 (1) A $9.3  115983  D   
Common Stock  6/23/2021  6/23/2021  S    15000 (2) D $37.74  100983  D   
Common Stock                 70  I  by Daughter (3)

Table II - Derivative Securities Beneficially Owned (e.g., puts, calls, warrants, options, convertible securities)
1. Title of Derivate Security
(Instr. 3)
2. Conversion or Exercise Price of Derivative Security 3. Trans. Date 3A. Deemed Execution Date, if any 4. Trans. Code
(Instr. 8)
5. Number of Derivative Securities Acquired (A) or Disposed of (D)
(Instr. 3, 4 and 5)
6. Date Exercisable and Expiration Date 7. Title and Amount of Securities Underlying Derivative Security
(Instr. 3 and 4)
8. Price of Derivative Security
(Instr. 5)
9. Number of derivative Securities Beneficially Owned Following Reported Transaction(s) (Instr. 4) 10. Ownership Form of Derivative Security: Direct (D) or Indirect (I) (Instr. 4) 11. Nature of Indirect Beneficial Ownership (Instr. 4)
Code V (A) (D) Date Exercisable Expiration Date Title Amount or Number of Shares
Non-Qualified Stock Option (right to buy)  $9.3  6/23/2021  6/23/2021  M        15000   7/1/2012  6/30/2021  Common Stock  15000  $0.0  0  D   

Explanation of Responses:
(1)  Acquired as a result of exercising a stock option that was scheduled to expire on June 30, 2021. The purchase reported on this Form 4 was effected pursuant to a Rule 10b5-1 Trading Plan adopted by the reporting person March 12, 2021.
(2)  Shares sold pursuant to a Rule 10b5-1 Trading Plan adopted by the reporting person on March 12, 2021.
(3)  The reporting person disclaims beneficial ownership of all securities held by his daughter, and this report should not be deemed an admission that the reporting person is the beneficial owner of such securities for purposes of Section 16 or for any other purpose.

Reporting Owners
Reporting Owner Name / Address
Relationships
Director 10% Owner Officer Other
BERTHELSEN SPENCER R
2855 GAZELLE COURT
CARLSBAD, CA 92010
X



Signatures
By: Patrick R. O'Neil, attorney-in-fact For: Spencer R. Berthelsen 6/24/2021
**Signature of Reporting Person Date
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