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CONFIDENTIAL TREATMENT REQUESTED
UNDER 17 C.F.R §§ 200.80(B)4, AND 240.24B-2 
 
EXHIBIT 10.59
 
December 15, 2014
 
B. Lynne Parshall, Chief Operating Officer
Isis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
Fax: (760) 918-3592

Re:  Amendment #1 to the SMA Agreement (“Amendment #1”)
Dear Lynne:
Reference is hereby made to that certain Development, Option and License
Agreement by and between Isis Pharmaceuticals, Inc. (“Isis”) and Biogen Idec
International Holding Ltd (“Biogen Idec”) dated January 3, 2012, as supplemented
and/or amended to date (the “SMA Agreement”).  Any capitalized terms not defined
herein shall have the meaning set forth in the SMA Agreement.
Biogen Idec and Isis hereby acknowledge and agree that the SMA Agreement is
hereby amended as follows:
1.           The definition of “Additional Development Plan Costs” in Appendix 1
of the SMA Agreement is hereby amended, superseded and replaced in its entirety
to read as follows:
“Additional Development Plan Costs” means [***].
For clarity, the amended definition of Additional Development Plan Costs shall
only apply with respect to Additional Development Plan Costs that are invoiced
by Isis pursuant to Section 1.4.2(a) of the SMA Agreement following the date of
this Amendment #1, and does not apply to any invoices for costs prior to the
date of this Amendment #1 or that have been agreed to pursuant to the letter
agreements between the parties dated January 27, 2014, August 13, 2014, October
7, 2014 and October 13, 2014.
2.           The following definitions are hereby added to Appendix 1 of the SMA
Agreement:
“CS3A Study” means the ISIS 396443-CS3A Clinical Study described in the
ISIS-SMNRx Development Plan.
 
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“CS3B Study” means the ISIS 396443-CS3B Clinical Study described in the
ISIS-SMNRx Development Plan.
“CS5 Study” means the ISIS 396443-CS5 Clinical Study described in the ISIS-SMNRx
Development Plan.
“CS12 Study” means the ISIS 396443-CS12 Clinical Study described in the
ISIS-SMNRx Development Plan.
“CS7 Study” means the ISIS 396443-CS7 Clinical Study described in the ISIS-SMNRx
Development Plan.
“Isis/Biogen Idec Additional Agreements” means the (i) DMPK Research,
Development, Option and License Agreement between the Parties dated June 27,
2012, (ii) Neurology Drug Discovery and Development Collaboration, Option and
License Agreement between the Parties dated December 10, 2012 and (iii) the
Strategic Neurology Drug Discovery and Development Collaboration, Option and
License Agreement between the Parties dated September 5, 2013, in each case, as
amended and/or restated from time to time.
3.           The definition of “PoC Trial” in Appendix 1 of the SMA Agreement is
hereby amended, superseded and replaced in its entirety to read as follows:
“PoC Trial” means (A) either (i) the CS3B Study, if the CS3B Study [***] set
forth in the protocol for the CS3B Study, or (ii) the CS4 Study, if the CS4
Study [***] set forth in the protocol for the CS4 Study, (B) completion of both
the CS3B Study and the CS4 Study, irrespective of whether any such Clinical
Studies [***] as set forth in the protocols for such Clinical Studies, or (C)
the CS3A Study if Biogen Idec notifies Isis that [***].
4.       The following revisions are made to the license fee payments and timing
under the SMA Agreement, in the event wherein a PoC Trial Completion Notice is
delivered either for [***] or [***]:
a.            Where the [***] Study is the First PoC Trial to Achieve [***]. 
Notwithstanding anything to the contrary in the SMA Agreement, in the event that
pursuant to Section 3.1.2 of the SMA Agreement Isis delivers a complete PoC
Trial Completion Notice to Biogen Idec with respect to the [***] Study before
the completion of the [***] Study, then:
(i) the Option Deadline (the “[***] Option Deadline”) shall be as set forth in
Section 3.1.3 of the SMA Agreement; and
(ii) the license fee set forth in Section 6.3 of the SMA Agreement shall be
$[***] (the “[***] License Fee”).
b.            Where the [***] Study is the First PoC Trial to Achieve [***]. 
Notwithstanding anything to the contrary in the SMA Agreement, in the event that
pursuant to Section 3.1.2 of the SMA Agreement Isis delivers a complete PoC
Trial Completion Notice to Biogen Idec with respect to the [***] Study before
the completion of the [***] Study, then:
 
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(i) Biogen Idec will pay Isis $[***] (the “[***] Clinical Success Fee”) within
[***] days after receipt of such complete PoC Trial Completion Notice;
(ii) the license fee set forth in Section 6.3 of the SMA Agreement shall be
$[***] (the “[***] License Fee”); and
(iii) the Option Deadline (the “[***] Option Deadline”) shall be the earlier of
(x) [***] days following the date upon which [***], or (y) [***] days following
Biogen Idec’s receipt of [***]; provided if at the time Biogen Idec receives
such [***], (A) the [***] Study [***] set forth in the protocol for the [***]
Study, and (B) Isis has [***], then the [***] Option Deadline will be [***] days
following the earlier of (I) the [***], or (II) the [***].
Together with Biogen Idec’s written notice to Isis that it is exercising the
Option and payment to Isis of the [***] License Fee by such [***] Option
Deadline, the Option shall be deemed exercised. If Biogen Idec does not provide
Isis a written notice that Biogen Idec is exercising the Option and pay Isis the
[***] License Fee by the [***] Option Deadline, then the SMA Agreement will
expire in accordance with Section 10.1.3 of the SMA Agreement.
c.            If the total amount of the [***] License Fee or the total sum of
the [***] License Fee and the [***] Clinical Success Fee, as applicable, paid to
Isis by Biogen Idec under this Amendment #1 equals $[***], an incremental
additional royalty of [***]% shall be applied to the portion of Annual Worldwide
Net Sales equal to or greater than $[***] (subject to any applicable royalty
reductions set forth in Section 6.6.2 of the SMA Agreement) until Isis receives
$[***] from this additional royalty. Once Isis has received such additional
$[***] more in royalties, the royalty rates will revert back to the original
royalty rates for the portion of Annual Worldwide Net Sales equal to or greater
than $[***] in Section 6.6.1 of the SMA Agreement, subject to any applicable
royalty rate reductions set forth in Section 6.6.2 of the SMA Agreement.

5.            If the decision is made to file an NDA and/or MAA based on data
from the [***] Study, the [***] Interim Data, and/or the [***] Interim Data, the
following provisions will apply:
a.            Where either an NDA and/or an MAA is Submitted Based on the [***].
Notwithstanding anything to the contrary in the SMA Agreement, Biogen Idec may
[***] request in writing that Isis submit an NDA to the FDA and/or an MAA to the
EMA based upon the data from the [***] Study.  Should Biogen Idec notify Isis in
writing that Isis should submit an NDA to the FDA and/or an MAA to the EMA based
upon the data from such [***] Study, then, subject to paragraphs 6 and 7 below,
Isis shall submit such NDA and/or MAA and then:
 
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(i)  The Option Deadline (the “[***] Option Deadline”) shall be the earlier of
(x) [***] days following the earliest date upon which [***], as applicable, or
(y) [***] days following Biogen Idec’s receipt of [***]; and
(ii) the license fee set forth in Section 6.3 of the SMA Agreement will be
$[***] (the “[***] License Fee”) and will be due by such [***] Option Deadline.
For the avoidance of doubt, the [***] Study shall not be deemed [***] unless
Biogen Idec notifies Isis that Biogen Idec wants Isis to submit either or both
an NDA to the FDA and/or an MAA to the EMA based upon the data from the [***]
Study.  [***].
b.            Where Biogen Idec Submits either an NDA and/or an MAA Based on the
[***] Interim Data. Notwithstanding anything to the contrary in the SMA
Agreement, in the event that Isis delivers interim data to Biogen Idec with
respect to the [***] Study (“[***] Interim Data”), Biogen Idec, at its sole
discretion, shall have [***] days in which to notify Isis that it will submit an
NDA to the FDA and/or an MAA to the EMA based upon such [***] Interim Data (the
“[***] Interim Data Filing Notice”). If Biogen Idec timely provides Isis a [***]
Interim Data Filing Notice, then the Option shall be deemed exercised, and
Biogen Idec will pay Isis the license fee of $[***] at the same time Biogen Idec
delivers the [***] Interim Data Filing Notice.
c.            Where either an NDA and/or an MAA is Submitted Based on the [***]
Interim Data. Notwithstanding anything to the contrary in the SMA Agreement, in
the event that Isis delivers interim data to Biogen Idec with respect to the
[***] Study (“[***] Interim Data”), Biogen Idec, at its sole discretion, shall
have [***] days in which to notify Isis in writing whether or not Biogen Idec
wants Isis to submit an NDA to the FDA and/or an MAA to the EMA based upon the
[***] Interim Data.  If, within such [***] day period, Biogen Idec notifies Isis
in writing that it wants Isis to submit an NDA to the FDA and/or an MAA to the
EMA based upon the [***] Interim Data (the “[***] Interim Data Filing Notice”),
then:
(i) Biogen Idec will pay Isis $[***] (the “[***] Interim Filing Fee”) at the
same time Biogen Idec delivers the [***] Interim Data Filing Notice;
(ii) the license fee set forth in Section 6.3 of the SMA Agreement shall be
$[***] (the “[***] Interim License Fee”); and
(iii) the Option Deadline (the “[***] Interim Option Deadline”) shall be the
earlier of (x) [***] days following the earliest date upon which [***], as
applicable, (y) [***] days following Biogen Idec’s receipt of a complete PoC
Trial Completion Notice for the [***], or (z) 60 days following Biogen Idec’s
receipt of [***] for both the [***] and the [***].
Together with Biogen Idec’s written notice to Isis that it is exercising the
Option and payment to Isis of the [***] Interim License Fee by the [***] Interim
Option Deadline, the Option shall be deemed exercised. If Biogen Idec does not
provide Isis a written notice that Biogen Idec is exercising the Option and pay
the [***] Interim License by the [***] Interim Option Deadline, then the SMA
Agreement will expire in accordance with Section 10.1.3 of the SMA Agreement.
 
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6.            In all cases where Biogen Idec has requested Isis to submit (or
following Option exercise where Biogen Idec chooses to submit) an NDA and/or MAA
for filing under this Amendment #1, Biogen Idec shall be responsible for [***]
and the IND-holder at the time of such filing (either Biogen Idec or Isis) shall
be responsible for submitting such NDA to the FDA and/or such MAA to the EMA. 
If Isis is the IND-holder at the time of filing such NDA or MAA, Isis will
[***], but Biogen Idec may [***].  If Biogen Idec is the IND-holder at the time
of filing such NDA or MAA, Biogen Idec will [***]. Upon Biogen Idec’s request,
Isis will assist Biogen Idec in [***], and Biogen Idec [***] incurred by Isis in
providing such assistance; provided, however, that Isis shall be responsible for
[***].
Subject to the terms and conditions of this Amendment #1, Isis will not assert
any of the Licensed Technology against Biogen Idec or its successors or assigns
solely based on Biogen Idec preparing an NDA or MAA in accordance with this
Amendment #1.
7.            If Biogen Idec requests Isis submit an NDA or MAA based upon the
data from the [***] Study, delivers a [***] Interim Data Filing Notice or
delivers a [***] Interim Data Filing Notice, Isis shall as soon as practicable
(but no later than [***] days after such request or delivery) transfer all
regulatory documentation (including drafts), and the relevant Isis Know-How
(including Manufacturing and Analytical Know-How) to Biogen Idec pursuant to
Section 4.5 of the SMA Agreement.  In all cases where Biogen Idec exercises the
Option, as soon as practicable (but no later than [***] days after Biogen Idec
exercises its Option under this Amendment #1) transfer and assign the regulatory
filings, including the IND to Biogen Idec pursuant to Section 4.5 of the SMA
Agreement.
8.            If Biogen Idec receives a [***] based upon [***], the following
provisions shall apply:
a.            Biogen Idec shall be the sole and exclusive owner of such [***].
b.            In the event that Biogen Idec sells or otherwise transfers such
[***] to a Third Party, then any consideration received by Biogen Idec in
exchange for such [***] shall be [***] for purposes of Article 6 of the SMA
Agreement. Biogen Idec and Isis will mutually agree on the [***] for purposes of
this paragraph 8(b).
c.            Biogen Idec shall determine, in its sole discretion, whether to
[***] to a [***] or to [***] to a Third Party.  If Biogen Idec determines to
[***], then Biogen Idec shall [***].
9.            Biogen Idec hereby agrees to use Commercially Reasonable Efforts
to undertake the [***] Study and the [***] Study.
If you accept the terms and conditions set forth in this Amendment #1, please so
indicate by executing a copy of this letter and returning it to Biogen Idec. 
Upon execution by both Isis and Biogen Idec, this Amendment #1 shall be
considered part of the SMA Agreement (including Sections 12.11 and 12.17 of the
SMA Agreement) but, except as expressly provided above, shall not be deemed to
modify or amend any provision of the SMA Agreement.  All other provisions of the
SMA Agreement will remain in full force and effect.
 
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This Amendment #1 may be executed in counterparts, each of which will be deemed
an original, notwithstanding variations in format or file designation which may
result from electronic transmission, store and printing of copies of this
Amendment #1 from separate computers or printers.  Facsimile signatures and
signatures transmitted via electronic mail in PDF format will be treated as
original signatures.
 
[Signature page follows]
 
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Sincerely,
     
/s/ Richard Brudnick
   
Richard Brudnick
 
Senior Vice President, Corporate Development
 
BIOGEN IDEC MA INC.
     
/s/ Frederick Lawson
     
Frederick Lawson, Director
 
BIOGEN IDEC INTERNATIONAL GMBH

AGREED AND CONFIRMED ON BEHALF OF ISIS PHARMACEUTICALS, INC.:
 
By:
/s/ B. Lynne Parshall
   
Name:
B. Lynne Parshall
   
Title:
Chief Operating Officer
   
Date:
   

 
Cc:
Isis Pharmaceuticals, Inc.
 
2855 Gazelle Court
 
Carlsbad, CA 92010
 
Attention:  General Counsel
 
Fax:  (760) 268-4922

 
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