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EXHIBIT 10.1

CERTAIN IDENTIFIED INFORMATION HAS BEEN EXCLUDED FROM THE EXHIBIT BECAUSE IT IS
BOTH (I) NOT MATERIAL AND (II) WOULD BE COMPETITIVELY HARMFUL IF PUBLICLY
DISCLOSED.  SUCH EXCLUDED INFORMATION HAS BEEN MARKED WITH “[***]”.

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August 16, 2019

Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
Attention: Chris Henderson, VP, Neuromuscular and Movement Disorders

 
Re:
Amendment No. 1 to the Neurology III Agreement

Dear Chris:

Ionis and Biogen are parties to the New Strategic Neurology Drug Discovery and
Development Collaboration, Option and License Agreement dated April 19, 2018
(the “Neurology III Agreement”) between Ionis Pharmaceuticals, Inc. (“Ionis”)
and Biogen MA Inc. (“Biogen”).  Any capitalized terms not defined in this letter
agreement (the “Letter Agreement”) will have the meanings set forth in the
Neurology III Agreement, unless expressly specified otherwise.

Ionis and Biogen hereby acknowledge and agree that the Neurology III Agreement
is hereby amended as follows:

1.            The following new Section 1.2.3(g) is added to the Neurology III
Agreement:
 
1.2.3(g).    Expanded High Interest Targets.
 

(i)
The Parties, through the Neurology JRC, may add up to [***] gene targets to the
High Interest Target List, beyond the [***]-target limit set forth in Section
1.2.3(a), under this Section 1.2.3(g) (each, an “Expanded High Interest
Target”).

 

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Chris Henderson
August 16, 2019
Page 2 of 4

(ii)
Before adding an Expanded High Interest Target to the High Interest Target List,
the Parties must mutually agree upon and submit to the Neurology JRC for
approval a research plan that meets the requirements of either Section
1.2.3(g)(ii)(A) or Section 1.2.3(g)(ii)(B) (each, an “Expanded High Interest
Target Plan”) for each such proposed Expanded High Interest Target.

 

(A)
An Expanded High Interest Target Plan may consist of an initial plan to conduct
limited research by the Parties that clearly defines the scope of work to be
performed by each Party.  Ionis and Biogen will use Commercially Reasonable
Efforts to conduct their respective activities under the Expanded High Interest
Target Plan.

 

(B)
An Expanded High Interest Target Plan may consist of a Target Sanction Plan.

 

(iii)
The Neurology JRC will review and, in its discretion, approve the addition of a
proposed Expanded High Interest Target to the High Interest Target List along
with the Expanded High Interest Target Plan corresponding to such proposed
Expanded High Interest Target.

 

(iv)
With respect to each proposed Expanded High Interest Target, if the Neurology
JRC, in good faith, does not unanimously agree to (1) add such proposed Expanded
High Interest Target to the High Interest Target List and (2) adopt the Expanded
High Interest Target Plan corresponding to such proposed Expanded High Interest
Target, then the proposed Expanded High Interest Target will not be added to the
High Interest Target List under this Section 1.2.3(g).  Such gene target may be
added to the High Interest Target List in accordance with Section 1.2.3(b) or
may be pursued independently by the Parties in accordance with Section 1.2.3(f).

 

(v)
With respect to any Expanded High Interest Target Plan under Section
1.2.3(g)(ii)(A), once the Parties complete all work under such plan and present
the results of such research to the Neurology JRC or [***] days following
approval of such Expanded High Interest Target Plan by the Neurology JRC,
whichever is earlier, the Neurology JRC will have [***] days within which to
unanimously agree upon a Target Sanction Plan for such Expanded High Interest
Target.  If the Neurology JRC does not unanimously agree upon a Target Sanction
Plan for such Expanded High Interest Target within such [***]-day period, then
the Expanded High Interest Target will be removed from the High Interest Target
List.  Such gene target may be added to the High Interest Target List in
accordance with Section 1.2.3(b) or may be pursued independently by the Parties
in accordance with Section 1.2.3(f).

 

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Chris Henderson
August 16, 2019
Page 3 of 4

(vi)
An Expanded High Interest Target that is approved by the Neurology JRC to add to
the High Interest Target List will not be subject to the terms of Section
1.2.3(a), Section 1.2.3(b), or Section 1.2.3(d)(i) of this Agreement.

 

(vii)
Once approved by the Neurology JRC, an Expanded High Interest Target will become
a High Interest Target for all purposes under this Agreement except as expressly
set forth in this Section 1.2.3(g), and the Expanded High Interest Target Plan
approved by the Neurology JRC for such Expanded High Interest Target will become
part of the Neurological Disease Research Plan.

 

(viii)
If, on or after the [***] anniversary of the date an Expanded High Interest
Target was added to the High Interest Target List, such target remains or
becomes an Inactive Target, then, unless the Parties mutually agree through the
Neurology JRC that such Expanded High Interest Target may remain on the High
Interest Target List, such Expanded High Interest Target will automatically be
removed from the High Interest Target List and will no longer be an Expanded
High Interest Target.  However, during the remainder of the Research Term, such
target will remain a Neurology Target and the Parties may add such target to the
High Interest Target List in accordance with Section 1.2.3(b) or again add such
target to the High Interest Target List in accordance with this Section
1.2.3(g).

 

(ix)
The maximum number of Expanded High Interest Targets set forth in Section
1.2.3(g)(i) may be increased or decreased by the Neurology JRC, and any such
change will be reflected in the minutes of the meeting of the Neurology JRC
where such increase or decrease occurred and subsequently formalized in a letter
between the Parties.

 
2.            Section 1.14.4(a) is deleted and replaced in its entirety with the
following:
 

1.14.4(a).
review and approve amendments to the Core Research Plan and the Neurological
Disease Research Plan, as described in Section 1.2.2 and 1.2.3(d)(iv), and
review and approve Expanded High Interest Targets to add to the High Interest
Target List, as well as the Expanded High Interest Target Plans corresponding to
such Expanded High Interest Targets, as described in Section 1.2.3(g);

 
Except as expressly set forth in this Letter Agreement, nothing in this Letter
Agreement will otherwise modify or amend any provision of the Neurology III
Agreement.

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Chris Henderson
August 16, 2019
Page 4 of 4

This Letter Agreement may be executed in counterparts, each of which will be
deemed an original, notwithstanding variations in format or file designation
that may result from electronic transmission, storage and printing of copies of
this Letter Agreement from separate computers or printers.  Facsimile signatures
and signatures transmitted via electronic mail in PDF format will be treated as
original signatures.

If the terms of this Letter Agreement are acceptable to Biogen, please so
indicate by executing a copy of this Letter Agreement and returning it to Ionis.

Very truly yours,

/s/ Brett Monia
Brett Monia
Chief Operating Officer
IONIS PHARMACEUTICALS, INC.

AGREED TO AND CONFIRMED BY BIOGEN MA INC.:

By: /s/ Chris Henderson
Name: Chris Henderson
Title:   VP, Neuromuscular and Movement Disorders

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