Execution Copy   
 Exhibit 10.2

AMENDMENT #4 TO RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT
This AMENDMENT #4 TO THE RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT (this
"Amendment No. 4") is entered into and made effective as of the 10th day of
April, 2014 (the "Amendment No. 4 Effective Date") by and between Isis
Pharmaceuticals, Inc., a Delaware corporation, having its principal place of
business at 2855 Gazelle Court, Carlsbad, CA 92010 ("Isis"), and Glaxo Group
Limited, a company existing under the laws of England and Wales, having its
registered office at 980 Great West Road, Brentford London TW8 9GS, United
Kingdom ("GSK").  Isis and GSK are each referred to herein by name or as a
"Party" or, collectively, as "Parties."
RECITALS
Whereas, Isis and GSK are parties to the Research, Development and License
Agreement dated March 30, 2010, as amended (the "Agreement"); and
Whereas, Isis and GSK desire to amend certain terms of the Agreement solely with
respect to the Collaboration Program focused on the [***] (the "GSK-5 Program"),
including to extend the Collaboration Term for the GSK-5 Program to March 30,
2015, on the terms and conditions set forth herein.
Now, therefore, in consideration of the premises and mutual covenants herein
contained, and for other good and valuable consideration, the receipt and
sufficiency of which are hereby acknowledged, and solely with respect to the
GSK-5 Program, the Parties, intending to be legally bound, do hereby agree as
follows:
Capitalized terms used but not defined herein shall have the meaning ascribed to
such terms in the Agreement.
1.
GSK-5 Program – Natural History Study.

a.
The Parties will conduct the Natural History Study as part of the GSK-5
Development Plan. GSK and Isis [***] a clinical research organization ("CRO") to
conduct the Natural History Study, and Isis will thereafter negotiate and enter
into an agreement with such CRO for the conduct of such study with terms
reasonably acceptable to GSK (the "CRO Contract"), it being understood that GSK
will provide Isis comments to the terms of the CRO Contract, if any, within
[***] ([***]) Business Days of receiving a draft of such CRO Contract from Isis.
Notwithstanding the preceding sentence, and subject to Section 1.b and Section
1.c, if GSK and Isis cannot agree on a term in the CRO Contract, [***] will have
final decision-making authority with respect to such term (provided that, such
decision is in accordance with the GSK-5 Development Plan and would not result
in an increase in External Costs above [***]). For avoidance of doubt, nothing
in this Amendment No. 4 requires Isis to amend any agreement between Isis and
any Third Party CRO that is in effect as of the Amendment No. 4 Effective Date.
The Parties intend that the CRO Contract will be executed by Isis as soon as
reasonably practicable after the Amendment No. 4 Effective Date.  Such CRO
Contract will specify that [***] and that, as between GSK and Isis, [***]. Isis
will ensure that the CRO Contract includes provisions that [***] and [***].

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b.
Promptly after the Amendment No. 4 Effective Date, the Parties will agree upon a
protocol for the conduct of the Natural History Study (the "Initial Natural
History Study Protocol").  Isis shall be responsible for all of the costs for
the conduct of the mutually-agreed Natural History Study (excluding any costs
incurred by GSK), provided that Isis shall only be responsible for external
costs for the Natural History Study (the "External Costs") up to [***] ($[***])
(the "Isis Natural History Study Cost Cap"). GSK will use reasonable efforts to
[***] in accordance with the timeline included in the Natural History Study
protocol. GSK will be responsible for the payment of all External Costs that
exceed the Isis Natural History Study Cost Cap except to the extent such
excessive costs result from [***].

c.
Isis will not make any changes to the Initial Natural History Study Protocol or
authorize or direct the CRO to do any work that is outside the scope of the
Initial Natural History Study Protocol that would result in External Costs above
the Isis Natural History Study Cost Cap, without GSK's prior written consent.
GSK will not make any changes to the Initial Natural History Study Protocol or
authorize or direct the CRO to do any work that is outside the scope of the
Initial Natural History Study Protocol that would increase Isis's internal FTE
costs for the conduct of such Natural History Study as compared to Isis's
internal FTE costs for the conduct of the Initial Natural History Study Protocol
without Isis's prior written consent.

2.
GSK-5 Program – PoC Trial.

a.
Proof of Concept (PoC) Trial. The initial agreed-upon GSK-5 Development Plan is
attached to this Amendment No. 4 as Attachment 1. The Parties [***] as set forth
in the attached GSK-5 Development Plan.  The Parties will meet approximately
[***] ([***]) [***] after the [***] to evaluate the progress of the Natural
History Study, determine [***], discuss [***] the Natural History Study and
discuss [***] on the [***]. As soon as reasonably practicable and in no event
later than the [***] ([***]) day following the date when [***] ([***]) of the
subjects participating in the Natural History Study complete [***] ([***])
[***], the Parties will discuss in good faith and, subject to [***], will [***]
the final study design and endpoints for the multiple-dose portion of the PoC
Trial, which the Parties anticipate will be substantially in the form set forth
for the PoC Trial study design and endpoints in the initial GSK-5 Development
Plan.

b.
As soon as reasonably practicable, Isis will provide GSK a summary of the data
under the single-dose portion of the PoC Trial up to and including the [***]
([***]) day after the day on which the [***] in the single-dose portion of the
PoC Trial (the "[***]").  Provided Isis has delivered the [***] to GSK, Isis may
deliver to GSK a written notice stating Isis' desire to begin the multiple-dose
portion of the PoC Trial (a "Request to Continue").  Within [***] ([***]) days
after receipt of a Request to Continue, GSK will (subject to Section 2.c of this
Amendment No. 4 below) deliver to Isis a written notice ("Notice to Continue")
authorizing Isis to begin the multiple-dose portion of the PoC Trial pursuant to
either (i) [***], or (ii) [***].  GSK will specify in its Notice to Continue
whether the study design and endpoints for the multiple-dose portion of the PoC
Trial for which GSK has authorized Isis to proceed are as set forth in (i) or
(ii) above.  For clarity, if GSK has not received a Request to Continue, GSK may
deliver a Notice to Continue to Isis at any time.

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c.
If, by [***] ([***]) days after receipt of the Request to Continue, GSK has not
provided Isis a Notice to Continue, then GSK's Option with respect to the GSK-5
Program will automatically expire and, subject to Section 5.10 of the Agreement
(as amended by this Amendment No. 4), Isis will be free to develop and
commercialize any Compounds that were included in the GSK-5 Program on its own
or with a Third Party and, except as specified in Section 5.10 of the Agreement
(as amended by this Amendment No. 4), GSK will have no further rights to the
GSK-5 Program (including all Compounds included therein) and [***] will no
longer be a Collaboration Target. Following any expiration of an Option under
this Section 2.c, GSK will promptly transfer to Isis all data, results and
information related to the testing and studies in the GSK-5 Program in the
possession of GSK and its contractors to the extent such data, results and
information were generated by or on behalf of GSK under the Agreement (as
amended by this Amendment No. 4).

d.
Except as provided under Section 2.c of this Amendment No. 4, the multiple-dose
portion of the PoC Trial shall not be initiated until the final GSK-5
Development Plan, including the final study design and endpoints for the
multiple-dose portion of the PoC Trial (which shall be subject to [***]), have
been agreed upon. Following GSK's Option exercise, decision-making for the GSK-5
Program will be governed in accordance with Section 3.c.ii of this Amendment No.
4.

3.
GSK-5 Program –Costs.

a.
Development Costs Paid by Isis. Isis will be responsible for, and will use
Commercially Reasonable Efforts to perform, Isis' activities under the GSK-5
Development Plan and will be responsible for all costs and expenses associated
therewith, except to the extent such costs and expenses have otherwise been
allocated to GSK under Section 1, Section 3.c or Section 5 of this Amendment No.
4.

b.
Manufacturing Costs Paid by Isis.  Subject to Section 5 of this Amendment No. 4
and until GSK exercises its Option for the GSK-5 Program in accordance with the
Agreement (as amended by this Amendment No. 4), Isis will be solely responsible
for the costs and expense for the Costs of Goods for the GSK-5 Development Plan.
As included herein, "Cost of Goods" means [***].

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c.
Development Costs Paid by GSK.

i.
Before Option Exercise. Until GSK exercises its Option for the GSK-5 Program in
accordance with the Agreement (as amended by this Amendment No. 4), GSK will be
responsible for and will use Commercially Reasonable Efforts to perform the
activities allocated to GSK under the GSK-5 Development Plan, and shall be
responsible for payment of all costs and expenses related to GSK's conduct of
such activities. In addition, GSK will be responsible for External Costs above
the Isis Natural History Study Cost Cap as set forth in Section 1.b of this
Amendment No. 4, and for any Additional Costs resulting from Approved Changes. 
If Additional Costs result from Approved Changes (excluding changes to the
Natural History Study), then Isis will deliver to GSK [***] an invoice for such
portion of the Additional Costs that is allocated for the activities [***]
[***], and GSK will pay each such invoice within [***] ([***]) days after GSK's
receipt.

ii.
After Option Exercise. Without limiting the terms set forth in the Agreement,
after GSK exercises its Option for the GSK-5 Program, GSK will be solely
responsible for and will have sole decision making authority over all
Development and Commercialization activities for the GSK-5 Program; provided,
however, that Isis will continue to be responsible for the completion of the PoC
Trial in accordance with the GSK-5 Development Plan in place at the time of such
Option exercise, including payment of the costs and expenses associated
therewith except to the extent such costs and expenses have otherwise been
allocated to GSK under Section 1, Section 3.c or Section 5 of this Amendment No.
4, and Isis will continue to be responsible for all activities allocated to Isis
under the GSK-5 Development Plan, including completion of reports and other
activities allocated to Isis under such GSK-5 Development Plan.  In addition,
after such Option exercise by GSK, GSK will be solely responsible for all costs
and expenses associated with Development, Manufacture and Commercialization of
Licensed Compounds and related Licensed Products from the GSK-5 Program,
excluding those costs and expenses for those activities for which Isis is
responsible under the GSK-5 Development Plan, or for which Isis is otherwise
responsible to provide at no cost to GSK under Section 4.2 of the Agreement.

4.
Option.

a.
Following GSK's receipt of (i) a notice from Isis that the PoC Trial is
Completed, and (ii) the PoC Data Package (as defined in this Amendment No. 4)
for the GSK-5 Program (such notice and package, the "GSK-5 PoC Trial Completion
Package"), GSK will provide written notice to Isis of its decision whether to
exercise its Option to the GSK-5 Program on or before 5:00 p.m. (Eastern time)
on the [***] day following GSK's receipt of the GSK-5 PoC Trial Completion
Package (the "GSK-5 Option Deadline").  If GSK does not provide written notice
to Isis of GSK's exercise of the GSK Option for the GSK-5 Program before the
GSK-5 Option Deadline, then GSK's Option to the GSK-5 Program will expire and,
subject to Section 5.10 of the Agreement (as amended by this Amendment No. 4),
Isis will be free to Develop and Commercialize any Compounds that were included
in the GSK-5 Program on its own or with a Third Party and, except as specified
in Section 5.10 of the Agreement (as Amended by this Amendment No. 4), GSK will
have no further rights to the GSK-5 Program (including all Compounds included
therein) and [***] will no longer be a Collaboration Target. Following any
expiration of an Option under this Section 4, GSK will promptly transfer to Isis
all data, results and information related to the testing and studies in the
GSK-5 Program in the possession of GSK and its contractors to the extent such
data, results and information were generated by or on behalf of GSK under the
Agreement (as amended by this Amendment No. 4).

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b.
Early Exercise of an Option. For the avoidance of doubt, notwithstanding
anything to the contrary in this Amendment No. 4 or in the Agreement, GSK will
have the right to exercise its Option for the GSK-5 Program prior to GSK's
receipt of a GSK-5 PoC Trial Completion Package in accordance with the terms of
the Agreement (as amended by this Amendment No. 4).

5.
Material Amendments to the GSK-5 Development Plan for the PoC Trial.

a.
Overview. As of the Amendment No. 4 Effective Date, the Parties have agreed to
the GSK-5 Development Plan (which is attached hereto as Attachment 1).

b.
Material Amendments. Subject to Section 5.d of this Amendment No.4, no Material
Amendments may be made without both Parties' prior written consent.  If any
Regulatory Authority requires or, based on feedback from a Regulatory Authority,
either Party requests a change to the PoC Trial or the GSK-5 Development Plan
that would require the Parties to make Material Amendment to the GSK-5
Development Plan to effect such a change, the Parties will use good faith and
commercially reasonable efforts to mutually agree on such Material Amendment
(including any associated Additional Costs and payment schedule thereof) within
[***] ([***]) days of receiving such proposed change from such Regulatory
Authority or a Party.

c.
Material Amendments Process.

i.
If the Parties mutually agree to make such a Material Amendment (excluding
Material Amendments to the Natural History Study) (including any associated
Additional Costs and the payment schedule thereof), such proposed Material
Amendment shall be deemed an Approved Change, and the GSK-5 Development Plan
will be amended to expressly incorporate such Approved Change.  Thereafter, Isis
and GSK (as applicable) will continue to conduct the GSK-5 Development Plan in
accordance with such amended GSK-5 Development Plan.

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ii.
If, despite the Parties' good faith and Commercially Reasonable Efforts, the
Parties cannot agree (i) on whether to make the proposed Material Amendment to
the GSK-5 Development Plan (including agreement on the scope of such proposed
Material Amendment or any associated Additional Costs, and the payment schedule
thereof) or (ii) whether such proposed amendment qualifies as a Material
Amendment, in each case, within [***] ([***]) days of receiving such proposed
change from such Regulatory Authority or a Party, the dispute will be promptly
(but no later than [***] days after the end of such [***] ([***]) day period)
referred to the [***]. If the [***] cannot resolve the matter within [***]
([***]) Business Days after receiving such dispute then, subject to Section 2.c
of this Amendment No. 4, the Parties will continue the activities under the
GSK-5 Program (including the PoC Trial) under the then-current GSK-5 Development
Plan, until such matter is resolved by the Parties (if ever) or the GSK-5
Program is terminated in accordance with the Agreement or this Amendment No. 4. 
Notwithstanding anything to the contrary in the Agreement or this Amendment No.
4, [***] with respect to changes to the study design and endpoints for the
multiple-dose portion of the PoC Trial, provided that (i) changes made as a
result of [***] shall be deemed Approved Changes for which [***] and (ii) with
respect to the multiple-dose portion of the PoC Trial, [***] to (x) [***], (y)
[***], or (z) [***].

d.
Non-Material Amendments. Isis will consider in good faith any changes to the
GSK-5 Development Plan that are requested by GSK that do not require the Parties
to make a Material Amendment to the GSK-5 Development Plan to affect such a
change.  Isis shall have the ability to make any changes to the GSK-5
Development Plan that do not require the Parties to make a Material Amendment to
the GSK-5 Development Plan to affect such a change without the prior consent of
GSK, provided, that such changes [***].

e.
The process for Approved Changes as set forth in this Section 5 shall not apply
to Approved Changes for the Natural History Study, which are addressed
exclusively by Section 1 of this Amendment No. 4.

6.
Financial Provisions. The following revised financial provisions will apply
solely to the GSK-5 Program:

a.
Milestone Payments for First Achievement of Development Milestone Event. Solely
with respect to a Compound under the GSK-5 Program that first achieves a
Development Milestone Event by or on behalf of GSK or its Affiliates or
Sublicensees, Column 1 of Table 2 set forth in Section 5.5.1 (Milestone Payments
for First Achievement of Development Milestone Event) of the Agreement is hereby
deleted in its entirety and replaced with Table 2A below.

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Table 2A
Development Milestone Events for the GSK-5 Program
 
Milestone Payment
 
[***]
[***]
[***]
[***]
[***]
[***]
[***]
 
[***]
[***]
[***]
[***]
[***]
[***]*
[***]
[***]*
[***]
 
Total Development Milestone Payments for the GSK-5 Program
[***]

*[***].
For avoidance of doubt, except as expressly amended by this Amendment No. 4, the
terms and conditions of Section 5.5.2 of the Agreement continue to apply to the
GSK-5 Program. Isis understands and acknowledges that, as of the Amendment No. 4
Effective Date, [***].
b.
GSK-5 Program Option Exercise Fee. Upon the exercise by GSK of the Option for
the GSK-5 Program, if exercised by GSK in accordance with the Agreement (as
amended by this Amendment No. 4), in lieu of the [***] ([***]) Option exercise
fee set forth in Column 1 of Table 1 in Section 5.4 (Option Exercise Fees) of
the Agreement, GSK will pay Isis an Option exercise fee of [***] ([***]) for the
GSK-5 Program.  Such Option Exercise Fee will be paid within [***] ([***]) days
after receipt by GSK of an invoice sent from Isis on or after such Option
exercise under the Agreement (as amended by this Amendment No. 4).

c.
Milestone Payments for First Achievement of Sales Milestone Event. Solely with
respect to a Licensed Product under the GSK-5 Program that first achieves the
listed events (as set forth in Table 4A below)  by or on behalf of GSK, its
Affiliates or Sublicensees, Table 4 set forth in Section 5.7.1 (Milestone
Payments for First Achievement of Sales Milestone Event) of the Agreement is
deleted in its entirety and replaced with Table 4A below:

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Table 4A
 
GSK-5 Sales Milestones for each Licensed Product in the GSK-5 Program
 
Milestone Payment
[***] in worldwide Annual Net Sales
 
[***]
[***] in worldwide Annual Net Sales
 
[***]
[***] in worldwide Annual Net Sales
 
[***]
[***] in worldwide Annual Net Sales
 
[***]
 
Total GSK-5 Sales Milestone Payments for the GSK-5 Program
 
[***]

7.
GSK-5 Program Royalties.  Solely with respect to the Licensed Products under the
GSK-5 Program sold by GSK, its Affiliates or Sublicensees, Table 5 set forth in
Section 5.9.1 (GSK Patent Royalty) of the Agreement is deleted in its entirety
and replaced with Table 5A below:

Table 5A
Worldwide Annual Net Sales of each Licensed Product in the GSK-5 Program
Royalty Rate
For the portion up to and including $[***]
 
[***]%
 
For the portion above $[***] and up to and including $[***]
 
[***]%
For the portion above $[***]
 
[***]%

 
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8.
GSK-5 Program Reverse Royalties.  Solely with respect to any GSK-5 Program
Discontinued Products, Table 6 set forth in Section 5.10.1 (Reverse Royalty for
Discontinued Products) of the Agreement is deleted in its entirety and replaced
with Table 6A below:

Table 6A
Development/Regulatory Status of Discontinued Product at time of reversion under
this Agreement
 
Applicable Royalty Rate on worldwide Annual Net Sales of Discontinued Product
Discontinued Products for which GSK has paid Isis the [***] milestone payment
 
[***]%
 
After [***] but prior to [***]
 
[***]%
After [***] but prior to [***]
 
[***]%
After [***]
 
[***]%

9.
No Impact on Other Collaboration Programs. Except as otherwise expressly amended
by this Amendment No. 4, the Agreement remains in full force and effect in
accordance with its terms. For the avoidance of doubt, this Amendment No. 4 is
solely intended to modify certain terms of the Agreement regarding the GSK-5
Program, and does not amend the Agreement in any way with respect to the other
Collaboration Programs.

10.
GSK's Right to Terminate for Convenience. This Section 10 of this Amendment No.
4 supersedes and replaces Section 9.2.1 of the Agreement with respect to the
GSK-5 Program, including GSK's right to terminate the GSK-5 Program under
Section 9.2.1 of the Agreement.  In lieu of GSK's right to terminate under
Section 9.2.1 of the Agreement, at any time following the Amendment No. 4
Effective Date, GSK will be entitled to terminate the Agreement (as amended by
this Amendment No. 4) with respect to the GSK-5 Program by providing Isis ninety
(90) days prior written notice; provided however, if GSK terminates the
Agreement (as amended by this Amendment No. 4) with respect to the GSK-5 Program
and at the effective date of such termination, Isis had spent in Development of
the GSK-5 Program (including actual external costs and Isis' good faith estimate
of its internal FTE costs) at least an amount equal to (a) [***] ([***]) plus
(b) [***], then if such notice of termination by GSK is:

(i)
before [***] for the GSK-5 Program and [***], GSK will pay Isis [***] percent
([***]%) of the milestone payment for [***] for the GSK-5 Program and [***]
percent ([***]%) of the milestone payment for [***],

(ii)
before [***] for the GSK-5 Program but after [***], GSK will pay Isis [***]
percent ([***]%) of the milestone payment for [***] for the GSK-5 Program,

(iii)
 after [***] for the GSK-5 Program but before [***], GSK will pay Isis [***]
percent ([***]%) of the milestone payment for [***],

(iv)
 after [***] for the GSK-5 Program and after [***] but before [***], GSK will
pay Isis [***] percent ([***]%) of the milestone payment for [***],

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(v)
after [***], GSK will pay Isis [***] percent ([***]%) of the milestone payment
for [***]; provided, that:

(A) if the [***] does not occur within [***] ([***]) months of such notice of
termination by GSK, then [***]: (a) such [***], minus the sum of: (b) [***], and
(c) [***]; or

(B) if the [***] occurs within [***] ([***]) months of such notice of
termination by GSK, and [***], then [***]; or

(C) if the [***] occurs within [***] ([***]) months of such notice of
termination by GSK, and [***], Isis will [***].

Notwithstanding the foregoing, if under the scenarios set forth in either
Section 10.v.A or Section 10.v.B above [***] prior to the end of the [***]
([***]) month period, then [***].
Following Isis's receipt of a notice of termination from GSK under this Section
10 of Amendment No. 4, Isis will invoice GSK for the appropriate payment due
under clauses (i)-(v) of this Section 10 of Amendment No. 4, as applicable, and
GSK will make the applicable payments under clauses (i)-(v) of this Section 10
within [***] days of receipt of such invoice.
Subject to Section 9.3.4 and Section 9.3.5 of the Agreement, as amended by this
Amendment No. 4, immediately following such termination notice date, GSK's
obligations under Section 5.5 through Section 5.9 of the Agreement (as amended
by this Amendment No. 4) will cease. Notwithstanding the foregoing, in the event
GSK believes in good faith that there are safety concerns with respect to the
GSK-5 Program or a Licensed Product under the GSK-5 Program, which concerns
merit the immediate termination of the GSK-5 Program or such Licensed Product,
GSK will have the right to terminate this Amendment No. 4 and the Agreement with
respect to the GSK-5 Program or such Licensed Product, as applicable,
immediately upon written notice to Isis and without a [***] ([***]) day notice
period for termination and [***].  This Section 10 shall survive the termination
of this Amendment No. 4 or the Agreement for purposes of determining the
applicable payment, if any, due by GSK as a result of such termination.
11.
Special Consequences for Voluntary Termination by GSK under Section 10 of this
Amendment No. 4.  In the event of a termination with respect to the GSK-5
Program under Section 10 of this Amendment No. 4, then:

a.
the licenses granted by Isis to GSK under the Agreement with respect to the
GSK-5 Program will terminate and GSK, its Affiliates and Sublicensees will cease
selling all Licensed Products from the GSK-5 Program; provided that GSK, its
Affiliates and Sublicensees will have the right to sell any remaining inventory
of such Licensed Products over a period of no greater than [***] ([***]) months
after the effective date of such termination and GSK will pay Isis royalties in
accordance with Section 7 of this Amendment No. 4 on the Net Sales of such
inventory of Licensed Products;

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b.
GSK will perform the obligations under Section 4.2.1 of the Agreement for the
GSK-5 Program, as though such obligations under Section 4.2 of the Agreement
were obligations owed by GSK to Isis, to the extent applicable and in GSK's
Control mutatis mutandis; and

c.
except as explicitly set forth in this Section 11, or Sections 9.3.3, 9.3.4 or
9.3.5 of the Agreement, GSK will have no further rights and Isis will have no
further obligations with respect to the GSK-5 Program.

For clarity, (i) this Section 11 of the Amendment No. 4 supersedes and replaces
Section 9.3.2 of the Agreement solely with respect to a voluntary termination by
GSK with respect to the GSK-5 Program, (ii) Section 9.3.2 of the Agreement will
not apply to GSK's voluntary termination with respect to the GSK-5 Program under
Section 10 of this Amendment No. 4, and (iii) Section 9.3.2 of the Agreement
will continue to apply in the case of a termination by Isis under Section 9.2.2
or 9.2.3 of the Agreement.
12.
Collaboration Term. Solely with respect to the GSK-5 Program, notwithstanding
anything to the contrary in the Agreement, the Collaboration Term for the GSK-5
Program is extended such that it ends on March 30, 2015.

13.
Definitions.  Capitalized terms not otherwise defined herein will have the
meanings given in the Agreement. For purposes of this Amendment No. 4, the
following capitalized terms will have the following meanings:

a.
"Additional Costs" means, [***].

b.
"Approved Changes" means any changes (including duration of dosing, additional
studies, additional endpoints, additional analysis, additional drug supply,
etc.) to the GSK-5 Development Plan (i) that are requested by a Party or
required by a Regulatory Authority, (ii) that are required to be agreed upon by
the Parties under this Amendment No. 4, and (iii) that are in fact agreed upon
by GSK and Isis in accordance with this Amendment No. 4 or are decided through
[***] final decision making authority under Section 5.c. of this Amendment No.
4.  For the avoidance of doubt, changes made to the Natural History Study in
accordance with the terms of Section 1 of this Amendment No. 4 and changes made
to the GSK-5 Development Plan that do not result in a Material Amendment shall
not be considered "Approved Changes" as that term is used in this Amendment No.
4.

c.
"Complete", "Completed", or "Completion" means the point in time at which the
primary database lock for the study data for the PoC Trial has occurred and the
data generated based on that primary database lock under the statistical
analysis plan for the PoC Trial are available.

d.
"Cost of Goods" has the meaning set forth in Section 3.b of this Amendment No.
4.

e.
"CRO" has the meaning set forth in Section 1.a of this Amendment No. 4.

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f.
"CRO Contract" has the meaning set forth in Section 1.a of this Amendment No. 4.

g.
"External Costs" has the meaning set forth in Section 1.b. of this Amendment No.
4.

h.
"GSK-5 Development Plan" means the Development plan attached to this Amendment
No. 4 as Attachment 1, which may be amended from time to time pursuant to
Section 5 of this Amendment No. 4.

i.
"GSK-5 Option Deadline" has the meaning set forth in Section 4 of this Amendment
No. 4.

j.
"GSK-5 PoC Trial Completion Package" has the meaning set forth in Section 4 of
this Amendment No. 4.

k.
"GSK-5 Program" has the meaning set forth in the recitals.

l.
[***]

m.
[***]

n.
[***]

o.
"Material Amendment" means an amendment to one (1) or more of the bullet-point
items set forth in the GSK-5 Development Plan included in Appendix A, attached
to this Amendment No. 4 and incorporated herein by reference.

p.
"Natural History Study" means a study intended to follow the natural progression
of [***] in patients with the [***], as more fully described in Attachment 1.

q.
"Natural History Study Cost Cap" has the meaning set forth in Section 1.b. of
this Amendment No. 4.

r.
"PoC Data Package" means, with respect to the GSK-5 Program Development
Candidate, (i) [***], (ii) [***], (iii) [***], (iv) [***], (v) copies of all
filings submitted to Regulatory Authorities, (vi) [***], and (vii) [***].  In
the event that GSK elects to exercise its early Option to the GSK-5 Program in
accordance with the Agreement (as amended by this Amendment No. 4), the PoC Data
Package will be interpreted to mean the items set forth in this Section 13.r (i)
through (vii) to the extent such items are available at the time that GSK
notifies Isis of GSK's election to exercise such early Option.

s.
"PoC Trial" means a clinical study for the GSK-5 Program, consisting of a
two-part, multicenter, open-label study of the GSK-5 Development Candidate,
including single dose (part 1) and multiple dose (part 2) cohorts, as described
in the GSK-5 Development Plan.

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* - * - * - *
[Signature page follows]
 
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Execution Copy    Exhibit 10.2

IN WITNESS WHEREOF, the Parties have caused this Amendment No. 4 to be executed
by their duly authorized representatives as of the Amendment No. 4 Effective
Date.
Isis Pharmaceuticals, Inc.
By: /s/ B. Lynne
Parshall                                                                                    
Name: B. Lynne
Parshall                                                                                    
Title: Chief Operating
Officer                                                                                    
Date:                                                                                                                                

Glaxo Group Limited
By: /s/ Paul
Williamson                                                                                    
Name: Paul
Williamson                                                                                    
Title: Authorised Signatory for and on behalf
Of Edinburgh Pharmaceutical Industries Limited
Corporate Director
Date:                              
                                                                       

Execution Copy    Exhibit 10.2

Execution Copy    Exhibit 10.2

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Attachment 1
GSK – 5 Development Plan
[***]

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