AMENDMENT #6 TO RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT

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Execution Copy

CONFIDENTIAL TREATMENT REQUESTED

UNDER 17 C.F.R §§ 200.80(B)4, AND 240.24B-2

Exhibit 10.2

AMENDMENT #6 TO RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT

This AMENDMENT #6 TO THE RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT (this “Amendment No. 6”) is entered into and made effective as of the 2^nd day of September, 2015 (the “Amendment No. 6 Date”) by and between Isis Pharmaceuticals, Inc., a Delaware corporation, having its principal place of business at 0000 Xxxxxxx Xxxxx, Xxxxxxxx, XX 00000 (“Isis”), and Glaxo Group Limited, a company existing under the laws of England and Wales, having its registered office at 000 Xxxxx Xxxx Xxxx, Xxxxxxxxx, Xxxxxx XX0 0XX, Xxxxxx Xxxxxxx (“GGL”), and Glaxosmithkline intellectual property development limited, a company existing under the laws of England and Wales, having its registered office at 000 Xxxxx Xxxx Xxxx, Xxxxxxxxx Xxxxxx XX0 0XX, Xxxxxx Xxxxxxx (“GSK IPDL”). GGL and GSK IPDL are referred to together as (“GSK”). Isis and GSK are each referred to herein by name or as a “Party” or, collectively, as “Parties.”

RECITALS

Whereas, Isis and GGL are parties to the Research, Development and License Agreement dated March 30, 2010, as amended (the “Agreement”) and GGL has sub-licensed its intellectual property rights under the Agreement to GSK IPDL;

Whereas, Isis and GGL entered into that certain Amendment #2 to the Research, Development and License Agreement dated October 30, 2012 (the “TTR FAP Amendment”) to amend the Agreement to more rapidly Develop the drug, ISIS-TTR_Rx (ISIS 420915), under the Rare Disease Program focused on the Collaboration Target, Transthyretin (the “TTR Program”), intended to enable ISIS-TTR_Rx to reach registration earlier than originally estimated; and

Whereas, Isis and GSK now desire to further amend the Agreement solely with respect to the TTR Program to, among other things, enable GSK to conduct a Phase 3 Trial of ISIS-TTR_Rx in patients with familial amyloid cardiomyopathy (FAC) and/or senile systemic amyloidosis (SSA) (the “Cardiomyopathy Phase 3 Trial”), on the terms and conditions as 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 TTR Program, the Parties, intending to be legally bound, do hereby agree as follows:

1.	TTR Program – Cardiomyopathy Drug Development Activities.

TTR Cardiomyopathy Development Plan; Xxxxxxxxxxxxxx Xxxxx 0 Trial. As of the Amendment No. 6 Date, the initial clinical study design for the Xxxxxxxxxxxxxx Xxxxx 0 Trial for the TTR Program is reflected in the TTR Cardiomyopathy Development Plan and further described in the other TTR Cardiomyopathy Registration-Directed Program Documents. The TTR Cardiomyopathy Development Plan is incorporated into and made an integral part of the TTR Development Plan for the overall TTR Program. GSK will [***] conduct the Xxxxxxxxxxxxxx Xxxxx 0 Trial in accordance with the TTR Cardiomyopathy Development Plan. The Parties intend the Xxxxxxxxxxxxxx Xxxxx 0 Trial to meet the requirements of a Phase 3 Trial to demonstrate therapeutic benefit in patients with FAC and SSA, and for the Xxxxxxxxxxxxxx Xxxxx 0 Trial and the TTR Cardiomyopathy Registration-Directed Program Documents to support registration filings and Approval of ISIS-TTR_Rx for FAC and/or SSA on a global basis. The Parties will mutually agree on any material changes to the TTR Cardiomyopathy Registration-Directed Program Documents in accordance with Section 7 of this Amendment No. 6.

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GSK’s Filing of the Xxxxxxxxxxxxxx Xxxxx 0 Xxxxx XXX. XXX will be the sponsor of the Xxxxxxxxxxxxxx Xxxxx 0 Trial and as such will file a separate IND (the “Cardiomyopathy IND”) for the Xxxxxxxxxxxxxx Xxxxx 0 Trial, which IND will reference Isis’ existing IND for ISIS-TTR_Rx. Isis will have the right to review and comment on the Cardiomyopathy IND prior to GSK filing it with any Regulatory Authority and will provide any comments within [***] ([***]) business days after receipt of the Cardiomyopathy IND. GSK will discuss such proposed changes with Isis, will consider Isis’ comments in good faith, [***]. Isis will execute, acknowledge and deliver such further instruments, and do all such other acts, as may be reasonably necessary in order for GSK to become the sponsor and IND-holder for the Xxxxxxxxxxxxxx Xxxxx 0 Trial.

Isis’ Support Activities for the Xxxxxxxxxxxxxx Xxxxx 0 Trial. Isis will provide support to GSK as reasonably requested by GSK from time to time for regulatory activities for the Xxxxxxxxxxxxxx Xxxxx 0 Trial, including without limitation assisting GSK with assembling the IND (which GSK will prepare and file) for the Xxxxxxxxxxxxxx Xxxxx 0 Trial, and sharing information on operational aspects of the conduct of the Xxxxxxxxxxxxxx Xxxxx 0 Trial and the ISIS-TTR_RxStudy (the “Isis Cardiomyopathy Support Activities”). If GSK were to request support from Isis in addition to the Isis Cardiomyopathy Support Activities, GSK will pay Isis to provide such support [***].

ISIS-TTR_Rx Safety Reporting; Regulatory Coordination. Until [***], Isis will be and will remain the sponsor and IND-holder for ISIS-TTR_Rxfor the Phase 2 PoC Trial for the FAP indication (the “ISIS FAP IND”). Isis hereby grants a right of reference to GSK to cross reference the ISIS FAP IND, and Isis will take such additional actions as reasonably requested by GSK to allow GSK to exercise its right of reference to the ISIS FAP IND. Because GSK will be the sponsor of the Xxxxxxxxxxxxxx Xxxxx 0 Trial and will file the Cardiomyopathy IND for the Xxxxxxxxxxxxxx Xxxxx 0 Xxxxx, XXX and Isis agree to coordinate their respective ISIS-TTR_Rx Development and regulatory activities, [***], and as otherwise agreed in the applicable Safety Data Exchange Agreement. Notwithstanding the foregoing, the Parties agree that GSK will lead the regulatory interactions with the Regulatory Authorities with respect to the Xxxxxxxxxxxxxx Xxxxx 0 Trial; provided, [***] and will consider in good faith any proposals and comments made by Isis.

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[***], the Parties will develop and agree in writing on a drug safety information exchange agreement (the “Safety Data Exchange Agreement”) that, with respect to the Xxxxxxxxxxxxxx Xxxxx 0 Trial, will include [***] related to ISIS-TTR_Rx, sufficient to enable each Party to comply with its legal and regulatory obligations and internal processes and consistent with the terms of this Amendment No. 6 and the Agreement (as amended by this Amendment No. 6).

During the term of the Safety Data Exchange Agreement (which shall remain in effect until [***]), each Party will [***] report to the other Party (and provide documentation to such Party related to) any serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs), and any other information the other Party reasonably requires to comply with its legal and regulatory requirements as the sponsor under its respective IND for ISIS-TTR_Rx,in each case in accordance with the terms as set out in the Safety Data Exchange Agreement. Notwithstanding the foregoing, each Party will provide the other Party with [***] updates regarding adverse events and lab findings under any Clinical Study conducted by or on behalf of a Party for ISIS-TTR_Rx.

Notice of Completion of Xxxxxxxxxxxxxx Xxxxx 0 Xxxxx. XXX will deliver written notice to Isis within [***] ([***]) Business Days after the Xxxxxxxxxxxxxx Xxxxx 0 Trial is Complete and, together with such notice, will provide Isis with the data generated based on the [***] (such notice and data, the “Xxxxxxxxxxxxxx Xxxxx 0 Trial Completion Package”).

Decision Making. GSK will use its Commercially Reasonable Efforts to perform its activities designated under the TTR Cardiomyopathy Development Plan giving due consideration to the recommendations and advice of the TTR Project Team. GSK will have the final decision-making authority regarding [***].

Briefing the TTR Project Team. At each regularly scheduled meeting of the TTR Project Team, GSK will provide to the TTR Project Team [***].

TTR Program – Cardiomyopathy Drug Development Activities and Costs. GSK will be responsible for all of GSK’s activities under the TTR Cardiomyopathy Registration-Directed Program Documents [***], including conducting the Cardiomyopathy Phase 3 Trial. In addition, GSK will be responsible for paying [***].

3.	Manufacturing and Supply.

API Supply for the Xxxxxxxxxxxxxx Xxxxx 0 Trial. Isis will supply to GSK up to a total of [***] API of ISIS-TTR_RX in accordance with the terms set forth on SCHEDULE 3. Isis and GSK are discussing [***].

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Finished Drug Product Supply for the Xxxxxxxxxxxxxx Xxxxx 0 Xxxxx. XXX will manufacture and supply, [***], Finished Drug Product for the Xxxxxxxxxxxxxx Xxxxx 0 Trial, which, as of the Amendment No. 6 Date, the Parties anticipate will be manufactured by [***] at a [***].

4.	Option. GSK may exercise its Option to the TTR Program by providing written notice to Isis of its decision to exercise its Option to the TTR Program under Section 3.1 of the Agreement on or before 5:00 p.m. (Eastern time) on the [*] ([]) day following the [**] under scenarios (a)-(d) below:

GSK receives a Xxxxxxxx Xxxxx 0 PoC Trial Notice from Isis; or

GSK receives endorsement, in accordance with [***] to prepare an NDA filing for ISIS-TTR_Rx; or

The Xxxxxxxxxxxxxx Xxxxx 0 Trial is Complete; or

Both the Xxxxxxxxxxxxxx Xxxxx 0 Trial and the Phase 2 PoC Trial are Complete or have been terminated in accordance with Section 10.a or Section 10.b of this Amendment No. 6 or under Section 11a or Section 11b of the TTR FAP Amendment or terminated under Article 9 of the Agreement;

(the “Option Deadline”).

If GSK does not provide written notice to Isis to license the TTR Program before the Option Deadline, then GSK’s Option to the TTR Program will expire and, subject to the terms of this Amendment No. 6, Section 9 of the TTR FAP Amendment and the terms of the Agreement (as amended by this Amendment No. 6), Isis will be free to [***] that were included in the TTR Program on its own or with a Third Party.

Following the expiration of the Option to the TTR Program, or termination of the Agreement with respect to the TTR Program, or termination of the Agreement in its entirety, GSK will have no further obligations to conduct the Xxxxxxxxxxxxxx Xxxxx 0 Trial and such responsibility, following transfer of the study to Isis as set forth below, would thereafter be the sole responsibility of Isis. Promptly (but in any event within [***] ([***]) days) following the expiration or termination of GSK’s Option to the TTR Program, GSK and Isis would agree upon a transfer plan and appropriate timelines for each of the activities set forth below and would initiate such activities in a diligent manner:

(a)

transfer to Isis, [***], the necessary data (including manufacturing batch records and test results, and such other required manufacturing information, clinical study results and information from the Xxxxxxxxxxxxxx Xxxxx 0 Trial (including transferring the Cardiomyopathy IND and sponsorship of the Xxxxxxxxxxxxxx Xxxxx 0 Trial to Isis), and such [***] information in the TTR Program in the possession or control of GSK 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. 6);

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(b)

at Isis’ written request, deliver to Isis any remaining stock of API in GSK’s possession as of the date of such expiration or termination [***], and any remaining stock of Finished Drug Product in GSK’s possession as of the date of such expiration or termination at a cost equal to [***]; provided that Isis will be responsible for [***] with respect to the transfer of the remaining stock of API and Finished Drug Product to Isis;

(c)

If Isis determines in good faith that additional Finished Drug Product would be required for Isis to continue to conduct those activities planned to be conducted during the [***]-month period immediately following such expiration or termination of GSK’s Option to the TTR Program, in accordance with the then-current TTR FAC Development Plan, then upon written notice from Isis to GSK, GSK will (i) supply to Isis ([***]) an amount of additional Finished Drug Product sufficient to conduct those activities actually planned for the subsequent [***]-month period under the then-current TTR Cardiomyopathy Development Plan and (ii) at Isis’ request, transfer the manufacturing process used by GSK to manufacture such Finished Drug Product to [***]; and

(d)

With respect to GSK’s contractual relationship with Third Parties performing work for GSK for the Xxxxxxxxxxxxxx Xxxxx 0 Trial (including any contract research organizations and CMOs intended for use as commercial suppliers of Finished Drug Product), at Isis’ written request, GSK will [***] in establishing a relationship with such Third Party CMO and transferring activities under GSK’s contractual arrangements with such Third Party CMO to Isis. GSK will also [***] to assign to Isis any stand-alone contractual manufacturing agreements (or the portion of a contractual manufacturing agreement to the extent assignable in part) that GSK may have in place with such Third Party CMO that are specific to the Xxxxxxxxxxxxxx Xxxxx 0 Trial material (excluding any such agreements that cover any other GSK products or activities, or are part of a master agreement between such Third Party CMO and GSK).

6.	For the avoidance of doubt, these Sections 4 and 5 expressly supersede and replace Section 5 of the TTR FAP Amendment.

7.	Material Amendments to the TTR Cardiomyopathy Registration-Directed Program Documents.

Overview. As of the Amendment No. 6 Date, the Parties have agreed to the TTR Cardiomyopathy Development Plan (which is attached hereto as Attachment 1) and the Xxxxxxxxxxxxxx Xxxxx 0 Xxxxxxxx. XXX may make non-material changes to the TTR Cardiomyopathy Development Plan, in its discretion. Any other material or non-material changes proposed to be made to the TTR Cardiomyopathy Development Plan shall be determined in accordance with Section 7 (b) or (c) below, as applicable.

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Material Amendment Process. No material amendment to any TTR Cardiomyopathy Registration-Directed Program Document (each, a “Material Amendment”) may be made without both Parties’ prior written consent. If any Regulatory Authority requires or, based on [***] or otherwise at its discretion, either Party requests a material change to the Xxxxxxxxxxxxxx Xxxxx 0 Trial or any TTR Cardiomyopathy Registration-Directed Program Document that requires the Parties to make a Material Amendment to a TTR Cardiomyopathy Registration-Directed Program Document to affect such a change, the Parties will use good faith and commercially reasonable efforts to mutually agree on such a Material Amendment to such TTR Cardiomyopathy Registration-Directed Program Document within [***] ([***]) days of receiving such proposed change from such Regulatory Authority or a Party. If the Parties mutually agree to such a Material Amendment, GSK will continue to perform the Xxxxxxxxxxxxxx Xxxxx 0 Trial in accordance with such amended TTR Cardiomyopathy Registration-Directed Program Documents. If, despite the Parties’ good faith and commercially reasonable efforts, the Parties cannot agree (i) on such a Material Amendment to such TTR Cardiomyopathy Registration-Directed Program Document or (ii) whether such an amendment is a Material Amendment, in each case, within [***] ([***]) days of receiving such proposed change from such Regulatory Authority or at the recommendation of a Party, as applicable, 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:

if the dispute arose prior to the date [***], then [***]; or

ii.

if the dispute arose after the date [***], then [***].

Non-Material Amendments. GSK will consider in good faith any changes to any TTR Cardiomyopathy Registration-Directed Program Documents that are requested by Isis that do not require the Parties to make a Material Amendment to a TTR Cardiomyopathy Registration-Directed Program Document to affect such a change.

8.	Financial Provisions. [***], GSK will pay Isis the following amounts:

$[***] as a lump sum payment when [***] occurs;

$[***] as a lump sum payment when [***]; and

$[***] as a lump sum payment when [***].

For clarity, except as provided in Section 1.c, Section 10.c and Schedule 3 of this Amendment No. 6, no further payments shall be owed by GSK under this Amendment No. 6. [***]. Each time a milestone event listed in items (a) through (c) above is achieved, GSK will send Isis a written notice thereof promptly (but in any event no later than [***] Business Days) following the date of achievement of such milestone event and such payment will be due within [***] days of receipt by GSK of an invoice sent from Isis.

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No Impact on Other Collaboration Programs. Except as otherwise expressly amended by this Amendment No. 6, the Agreement remains in full force and effect in accordance with its terms. For the avoidance of doubt, this Amendment No. 6 is solely intended to modify certain terms of the Agreement regarding the TTR Program, and does not amend the Agreement in any way with respect to the other Collaboration Programs.

10.	Termination for a Safety Concern.

Required by Regulatory Authorities or Mutually Agreed. If a Safety Concern arises that causes (i) [***] or (ii) [***], then in each case [***] should be initiated within [***] ([***]) days after such request or agreement and GSK may terminate its Option to the TTR Program with [***] ([***]) days advance written notice.

Not Required by Regulatory Authorities or Mutually Agreed. If a Safety Concern arises that causes the Cardiomyopathy-DSMB, any Regulatory Authority, or GSK’s Global Safety Board to [***], the Parties will promptly (but no later than [***] ([***]) days after such inability to agree on the [***]) meet and confer to discuss such Safety Concern and use good faith efforts to resolve such Safety Concern. If, after such good faith discussions (including discussions with the Cardiomyopathy-DSMB), [***], GSK will have the right to terminate the Xxxxxxxxxxxxxx Xxxxx 0 Trial and/or the TTR Program by providing Isis written notice, which termination will become effective on the [***] ([***]) day following Isis’ receipt of such termination notice.

Consequences of Termination. If GSK terminates its Option to the TTR Program under Section 10.a or Section 10.b of this Amendment No. 6 or under Section 11a or Section 11b of the TTR FAP Amendment (i) GSK will have no obligation to make any further payments to Isis under this Amendment No. 6 (other than any payments that accrued prior to the effective date of any such termination), (ii) Isis will have no obligation to continue the Phase 2 PoC Trial or Xxxxxxxxxxxxxx Xxxxx 0 Xxxxx, (xxx) XXX will pay Isis $[***] to compensate Isis for its [***] costs only if Isis directs, by written notice within [***] ([***]) days after GSK’s termination notice, the clinical research organization that is engaged to conduct the Phase 2 PoC Trial to begin the process of terminating the Phase 2 PoC Trial, and (iv) GSK will pay Isis an amount equal to [***] only if, within [***] ([***]) days after GSK’s termination notice, Isis delivers written notice to GSK of Isis’ election to begin the process of terminating the Xxxxxxxxxxxxxx Xxxxx 0 Trial.

11.

Restriction on GSK’s Right to Terminate for Convenience. Except in accordance with Section 10.a or Section 10.b of this Amendment Xx. 0, Xxxxxxx 00x or Section 11b of the TTR FAP Amendment, or Section 9.2.2, Section 9.2.3(a) or Section 9.2.5 of the Agreement, GSK will not have the right to terminate the Agreement with respect to the TTR Program (or terminate this Amendment No. 6) until the [***]

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12.	Definitions. Capitalized terms not otherwise defined herein will have the meanings given in the Agreement. For purposes of this Amendment No. 6, the following capitalized terms will have the following meanings:

“API” means bulk active pharmaceutical ingredient manufactured in accordance with cGMP (unless expressly stated otherwise) for ISIS-TTR_Rx.

“Cardiomyopathy-DSMB” means the Data Safety Monitoring Board for the Xxxxxxxxxxxxxx Xxxxx 0 Trial.

“Cardiomyopathy-DSMB Charter” means, with respect to the Cardiomyopathy-DSMB for the Xxxxxxxxxxxxxx Xxxxx 0 Trial, any charter that governs the activities and duties of such Cardiomyopathy-DSMB and specifies its members.

“Cardiomyopathy IND” has the meaning set forth in Section 1.b.

“Cardiomyopathy Phase 3 Protocol” means the protocol No. ISIS 420915-CS entitled “A Randomised, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of GSK2998728 in Subjects with Transthyretin Amyloid Cardiomyopathy” (GSK study ID: 204650)” for the conduct of the Xxxxxxxxxxxxxx Xxxxx 0 Trial, as may be amended from time to time pursuant to Section 7 of this Amendment No. 6.

“Cardiomyopathy Phase 3 Trial” means, with respect to ISIS-TTR_Rx, the Phase 3, multicenter, double-blind, randomized, placebo-controlled study of ISIS-TTR_Rx in Cardiomyopathy patients_.

“Cardiomyopathy Phase 3 Trial Completion Package” has the meaning set forth in Section 1.f.

“Complete”, “Completed”, or “Completion” means[***].

“Dosing” or “Dosed” has the meaning set forth in Section 8.

“Finished Drug Product” means any drug product containing API as an active pharmaceutical ingredient in finished bulk form.

“Isis Cardiomyopathy Support Activities” has the meaning set forth in Section 1.c.

“ISIS-TTR_Rx” means the Compound known as ISIS 420915 and also known as GSK2998728.

“Material Amendment” has the meaning set forth in Section 7.b.

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“Option Deadline” has the meaning set forth in Section 4.

“Positive Phase 2 PoC Trial Notice” means, with respect to the Phase 2 PoC Trial, a written notice delivered by Isis to GSK containing (i) [***], and (ii) [***].

“Safety Concern” means [***]

“Safety Data Exchange Agreement” has the meaning set forth in Section 1.e.

“TTR Cardiomyopathy Development Plan” means the Development plan attached to this Amendment as Attachment 1, as may be amended from time to time pursuant to Section 7 of this Amendment No. 6.

“TTR Cardiomyopathy Registration-Directed Program Documents” means the TTR Cardiomyopathy Development Plan, the Xxxxxxxxxxxxxx Xxxxx 0 Protocol and the Cardiomyopathy-DSMB Charter.

“TTR FAP Amendment” has the meaning set forth in the Recitals.

“TTR Program” has the meaning set forth in the Recitals.

* - * - * - *[Signature page follows] * - * - * - *

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IN WITNESS WHEREOF, the Parties have caused this Amendment No. 6 to be executed by their duly authorized representatives as of the Amendment No. 6 Date.

Isis Pharmaceuticals, Inc.

By:	/s/ B. Xxxxx Xxxxxxxx

Name:	B. Xxxxx Xxxxxxxx

Title:	Chief Operating Officer

Date:

Glaxo Group Limited

By:	/s/ Xxxx Xxxxxxxxxx

Name:	Xxxx Xxxxxxxxxx

Title:	Authorised Signatory For and on behalf

Of Edinburgh Pharmaceutical Industries Limited

Corporate Director

Date:	9/1/15

Glaxosmithkline intellectual property development limited

By:	/s/ Xxxx Xxxxxxxxxx

Name:	Xxxx Xxxxxxxxxx

Title:	Authorised Signatory For and on behalf

Of Glaxo Group Limited

Corporate Director

Date:	9/2/15

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Attachment 1

TTR Cardiomyopathy Development Plan

[***]

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Schedule 3

TTR CARDIOMYOPATHY ISIS-TTR_RX API CLINICAL SUPPLY TERMS

The following terms shall apply to ISIS’s supply to GSK of API for the XXX Xxxxxxxxxxxxxx Xxxxx 0 Trial:

Isis will manufacture and supply to GSK up to a total of [***] kg of the bulk active pharmaceutical ingredient ISIS-TTR_RX to support the Cardiomyopathy Phase 3 Trial.

On or promptly after the Amendment Xx. 0 Xxxx, XXX shall issue a purchase order (“PO”) for [***] kg of ISIS-TTR_RX API. Upon receipt of a PO from GSK, Isis will begin activities for the manufacture of such ISIS-TTR_RX API and will deliver such ISIS-TTR_RX API to GSK within [***] ([***]) days at the latest, using Commercially Reasonable Efforts to provide such material in a shorter time frame of the receipt of such PO from GSK. Unless the Parties mutually agree otherwise, promptly following the first Dosing of the first patient in the TTR Xxxxxxxxxxxxxx Xxxxx 0 Trial, anticipated in the first half of 2016, GSK will issue a second PO for an additional [***] kg of ISIS-TTR_RX API. The terms as set forth herein shall apply equally to the second batch of ISIS-TTR_RX API ordered by GSK. The Parties acknowledge that various factors that are uncertain as of the Amendment No. 6 Date may impact the timing or the amount of the second batch of API required for the TTR Xxxxxxxxxxxxxx Xxxxx 0 Trial, and each Party agrees to discuss any such modifications in good faith at the time. For purposes of this Schedule 3 to Amendment No. 6, a “Purchase Order” or “PO” means the commercial document to be issued by GSK to place a firm order for a batch of ISIS-TTR_RX API to be manufactured and supplied to GSK under the terms and conditions of this Amendment No.6.

Pricing. The price for each [***] kg batch of ISIS-TTR_RX API will be $[***].

Terms of Payment. The purchase price for the ISIS-TTR_RX API shall be paid by GSK as follows:

Upon receipt of a PO from GSK, Isis shall invoice GSK for [***] percent ([***]%) of the total price named in Section 2 of this Schedule 3 of Amendment No. 6 for such batch, and GSK shall pay such invoiced amounts by wire transfer of immediately available funds within [***] ([***]) days of the month that is [***] ([***]) days following receipt of such invoice by GSK.

On or following delivery of the applicable batch of ISIS-TTR_RX API to GSK in accordance with the terms of this Schedule 3 of Amendment No. 6, Isis will invoice GSK for the remaining [***] percent ([***]%) of the price of such batch of ISIS-TTR_RX API and GSK will pay such invoiced amount within the [***] ([***]) days of the month that is [***] ([***]) days following receipt of such invoice by GSK.

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Audit Rights. Isis will procure and ensure that, for the duration of the TTR Program, GSK or its nominee shall have the right, on reasonable prior written notice and during normal business hours at times and dates mutually agreed in advance by the Parties, to enter and inspect the facilities and systems where any ISIS-TTR_RX API supplied under this Agreement is manufactured or stored in order to carry out a GMP, quality and/or compliance audit. This includes ISIS systems for management of their sub-contractors. The right of GSK to request an audit of ISIS sub-contractor facilities and systems is restricted to in the event of unfavorable regulatory findings or “for cause” audits. Isis will use its Commercially Reasonable Efforts to ensure that any corrective actions identified in any audit carried out pursuant to this Amendment No. 6, that the Parties mutually agree will be implemented by Isis, are implemented promptly.

Quality Standards

Promptly following execution of this Amendment No. 6, Isis and GSK have executed a Quality Agreement (the “Quality Agreement”) for the manufacture of ISIS-TTR_RX API under this Amendment No. 6.

Isis will manufacture and release the ISIS-TTR_RX API in accordance with the API Specification, US cGMP, the Quality Agreement and other applicable rules and regulations of all Regulatory Authorities and other regulatory agencies with jurisdiction over the manufacture, use or sale of the API, as then in effect, including, without limitation, stability requirements. If cGMP for the U.S. and its foreign equivalent differ, GSK will specify in writing which cGMP will apply. ISIS will be responsible for Manufacturing issues related to API safety and regulatory compliance. Each Party will promptly notify the other Party of any relevant new instructions or specifications required by a Regulatory Authority, and of other applicable regulations of which that Party becomes aware. The Parties will confer with each other with respect to the best means to comply with such requirement and will allocate any costs of implementing such changes [***]. The “API Specification” means the synthesis procedures as set forth in the specification, attached hereto as Appendix X.

“cGMP” means current practices for the Manufacture of the relevant API or material as required in relation to the relevant API at the time of Manufacture by Applicable Laws in the country in which the relevant API or material is Manufactured or to be commercialized, which (i) in the United States, includes the principles detailed in the U.S. Current Good Manufacturing Practices, 21 C.F.R. Parts 210 and 211; (ii) in the ICH region, includes the relevant International Conference on Harmonisation Quality Guidelines relating to good manufacturing practice; and/or (iii) in Europe or if the API is to be supplied to a country within Europe, the standards, rules, principles and guidelines of Good Manufacturing Practices for medicinal products set out in Directive 2001/83/EC (as amended by Directive 2004/27/EC), Directive 2003/94/EC and EudraLex – Volume 4 of the Rules Governing Medicinal Products in the European Union entitled "EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use".

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Isis will perform quality control testing as is specified in the API Specification and the Quality Agreement.

Certificate of Analysis

Isis will provide a Certificate of Analysis to GSK with the ISIS-TTR_RX API supplied hereunder (the “API COA”). Each Certificate of Analysis will contain the results of the analysis of ISIS-TTR_RX API as required in the API Specification, and will certify with respect to the shipment and lot (identified by lot number): (i) the quantity of the shipment, (ii) that the API delivered was Manufactured in accordance with the API Specification and in conformance with the applicable cGMP. The Certificate of Analysis will contain any information in addition to that required herein as may be required by the Regulatory Authority of the country of destination of ISIS-TTR_RX API or Product; provided, however, that GSK provides to Isis, in a timely manner, sufficient documentation and information that is necessary or useful and available to GSK, to enable Isis to conform with such requirements. Isis will provide the results of such analysis to GSK, along with any supporting data.

Isis will also make available for GSK’s review Isis’ Manufacturing records for the API, including its master and production batch records, for the purposes of assuring product quality and compliance with agreed-upon Manufacturing procedures.

ISIS-TTR_RX API Conformity. Within [***] ([***]) days after the Release Date (defined below) of the ISIS-TTR_RXAPI (such period, the “Assessment Period”), GSK will determine whether the ISIS-TTR_RX API conforms to the API Specification and the Master Batch Record (collectively the “API Requirements”). If GSK believes any shipment of ISIS-TTR_RX API does not conform to the API Requirements (“Non-conforming API”), then GSK will give Isis written notice thereof as soon as practicable but in no event later than the Assessment Period and will, unless otherwise directed by Isis, return the Non-conforming API for further testing by Isis. Failure to provide such written notice and return the Non-conforming API for further testing by Isis will constitute GSK’s acceptance of such API. If, after conducting its own testing, Isis agrees that the returned Non-conforming API does not meet API Requirements, then the provisions of Section 8 of this Schedule 3 of Amendment No. 6 will apply. In the event of unresolved inter-laboratory differences between the laboratory testing of the API conducted by or on behalf of GSK and Isis’ laboratory testing on the API, a mutually agreed upon independent testing facility shall resolve said discrepancies. The costs of such independent testing shall be borne by [***]. For purposes of this Agreement, on a API-by-API basis, “Release Date” means the date GSK has in its possession (i) the ISIS-TTR_RX API Certificate of Analysis, ISIS-TTR_RX API Certificate of Origin and Batch Record Package for such ISIS-TTR_RX APIs, and (ii) a notice from Isis that Isis’ quality department has released the ISIS-TTR_RX API to GSK and that such ISIS-TTR_RX API is available for shipment to GSK or its designee.

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Non-Conforming API; Replacement of Goods. If a batch of ISIS-TTR_RX API is determined to be Non-conforming ISIS-TTR_RX API (whether by agreement of Isis or by an independent expert as set forth above), all such Non-conforming ISIS-TTR_RX API will be either returned to Isis or destroyed, at GSK’s option and, subject to Section 10 of this Schedule 3 of Amendment No. 6, Isis will use its commercially-reasonable efforts to replace such Non-conforming ISIS-TTR_RX API as soon as reasonably practicable.

Batch Failure. If Isis encounters any unforeseen difficulties or hazards during the manufacturing of the ISIS-TTR_RX API that prevent Isis from successfully manufacturing such batch of ISIS-TTR_RX API in accordance with this Amendment No. 6 (including but not limited to the failure of such ISIS-TTR_RX API to conform to the warranty set forth in Section 12 of this Schedule 3 of Amendment No. 6), Isis will use its commercially reasonable efforts to manufacture a replacement batch of ISIS-TTR_RX API, such that GSK receives such ISIS-TTR_RX API as close to the originally-scheduled delivery date as possible.

10.

Costs Sharing for Replacement Batches of ISIS-TTR_RX API. Isis and GSK will share the costs of replacement of ISIS-TTR_RX API as a result of a Non-conforming batch under Section 8 of this Schedule 3 or as a result of a batch failure under Section 9 of this Schedule 3, as follows: Isis will be responsible for the [***] and [***] for such batch of API; and, to the extent [***], GSK will be responsible for the [***] and [***] ([***]); provided, however that GSK will not be responsible if such failure results from Isis’ gross negligence or willful misconduct.

11.

Title & Transportation. Title to the ISIS-TTR_RX API supplied by Isis under this Amendment No. 6 will vest in GSK upon [***]. Risk of loss passes simultaneously with title. Isis may deliver the applicable invoice to GSK for ISIS-TTR_RX API contemporaneously with delivery of ISIS-TTR_RX API. Isis will deliver the API [***] ([***]) [***]. GSK will take delivery of the API within [***] after notification by Isis to GSK that such API is ready for shipment.

12.

Representations and Warranties. Isis represents and warrants that, at the time of delivery, any ISIS-TTR_RX API supplied by Isis will (a) meet the API Specification and any specifications required by the Quality Agreement; (b) meet the standards of cGMP (for the ISIS-TTR_RX API) and (c) be conveyed with good title, free from any lawful security interest, lien or encumbrance.

Confidential

13.

Disclaimer Of Warranties: THE LIMITED WARRANTIES CONTAINED IN THIS DOCUMENT ARE THE SOLE WARRANTIES WITH RESPECT TO THE API AND ARE MADE EXPRESSLY IN LIEU OF AND EXCLUDE ANY IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE AND ALL OTHER EXPRESS OR IMPLIED REPRESENTATIONS AND WARRANTIES PROVIDED BY COMMON LAW OR STATUTE.

14.

Limitation Of Remedies. EXCEPT FOR CLAIMS RESULTING FROM GROSS NEGLIGENCE OR WILLFUL MISCONDUCT BY ISIS, GSK’S EXCLUSIVE REMEDY AND ISIS’ TOTAL LIABILITY TO GSK FOR CLAIMS (INCLUDING, WITHOUT LIMITATION, THOSE ARISING OUT OF STRICT LIABILITY AND BREACH OF WARRANTY) WITH RESPECT TO A BATCH OF ISIS-TTR_RX API SUPPLIED BY ISIS TO GSK UNDER THIS AMENDMENT NO. 6 IS EXPRESSLY LIMITED TO REPLACEMENT OF GOODS. NEITHER PARTY WILL BE UNDER ANY LIABILITY TO THE OTHER PARTY FOR ANY INCIDENTAL, CONSEQUENTIAL, SPECIAL, EXEMPLARY OR PUNITIVE DAMAGES EXCEPT IN THE EVENT OF WILLFUL MISCONDUCT OR FRAUD.

15.

Waiver of Claims for Defective Goods. ALL CLAIMS BY GSK ARISING FROM ANY DAMAGE, DEFECT OR SHORTAGE (INCLUDING, WITHOUT LIMITATION, THOSE ARISING OUT OF STRICT LIABILITY, BREACH OF WARRANTY AND NEGLIGENCE) OF THE ISIS-TTR_RX API WILL BE DEEMED WAIVED UNLESS MADE BY GSK IN WRITING AND RECEIVED BY ISIS WITHIN [***] DAYS OF THE LATER OF (A) RECEIPT OF THE Certificate of Analysis FOR THE ISIS-TTR_RX API, OR (B) WHEN SUCH DAMAGE, DEFECT OR SHORTAGE COULD HAVE BEEN REASONABLY DISCOVERED.

16.

Compliance with cGMPs; Monitoring of Records. Isis will monitor and maintain reasonable records respecting its compliance with cGMPs in the manner provided by the Quality Agreement, including the process of establishment and implementation of the operating procedures and the training of personnel as are reasonably necessary to ensure such compliance. Unless stated otherwise in the Quality Agreement, Isis will, at its expense and in accordance with Isis current record retention policy, store all associated cGMP testing and quality control records relating to a particular Statement of Work on site. GSK will be notified to determine whether the records may be destroyed, provided to GSK or continue to be stored at GSK’s request or expense.

17.

Regulatory Authority Inspections. At GSK’s request, Isis will authorize Regulatory Authorities to review related applications on GSK’s behalf. Isis will notify GSK within five days of all contacts with Regulatory Authorities (both written and verbal) related to each API. Isis will inform GSK of the result of any regulatory inspection which directly affects the Manufacture of an API, including any notice of inspection, notice of violation or other similar notice received by Isis affecting Manufacture, testing, storage or handling of an API. In the event of an FDA inspection that involves an API, GSK will be immediately informed of the issuance of the Notice of Inspection (FDA Form 482) and GSK reserves the right to be on site at Isis during the conduct of the inspection. If there are inspectional observations (FDA Form 000), XXX will be informed immediately and will have the opportunity to review and provide Isis with comments to Isis’ response. GSK will provide its comments to the response of these observations within five business days and Isis will not unreasonably refuse to include GSK’s comments in Isis’s response.

Confidential

18.

Regulatory Communications and Correspondence. All other communications from and to the FDA or other Regulatory Authorities related to the Manufacture of the API at the Facility will be handled in accordance with the terms and conditions of the Quality Agreement, or as otherwise agreed in writing by GSK and Isis.

19.

Regulatory Filings and Maintenance. During the Term of the Agreement, GSK will be solely responsible for preparing and submitting all required regulatory documents necessary for the API, including adverse drug experience reports, field alert reports, periodic reports and applications for renewals, variations, supplements and amendments. Isis will prepare and maintain all regulatory filings and manufacturing files, certificates, authorizations, data and other records that pertain to the Manufacture of the API, as further set forth in the Quality Agreement or as otherwise agreed in writing by GSK and Isis.

20.

Records. Subject to Applicable Laws, Isis will maintain the manufacturing records required by the terms and conditions of the Quality Agreement, or as otherwise agreed to in writing by GSK and Isis in the applicable Purchase Order. Isis agrees that, in response to any complaint, or in the defense by GSK of any litigation, hearing, regulatory proceeding or investigation relating to the manufacture of API, Isis will use reasonable efforts to make available to GSK during normal business hours and upon reasonable prior written notice, such Isis employees and records reasonably necessary to permit the effective response to, defense of, or investigation of such matters, subject to appropriate confidentiality protections. GSK will reimburse Isis for all out-of-pocket costs and expenses reasonably incurred by Isis in connection with the performance of Isis’ obligations under the immediately preceding sentence.

Confidential

Appendix X

API Specification

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Table of Contents

AMENDMENT #6 TO RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT

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