Document:

Exhibit 10.1

 

INDEMNITY AGREEMENT

 

THIS INDEMNITY AGREEMENT (the “Agreement”) is made and entered into this        day of                      by and between Isis Pharmaceuticals, Inc., a Delaware corporation (the “Corporation”), and [name]. (“Agent”).

 

RECITALS

 

WHEREAS, Agent performs a valuable service to the Corporation in his  capacity as [Title];

 

WHEREAS, the stockholders of the Corporation have adopted bylaws (the “Bylaws”) providing for the indemnification of the directors, officers, employees and other agents of the Corporation, including persons serving at the request of the Corporation in such capacities with other corporations or enterprises, as authorized by the Delaware General Corporation Law, as amended (“Delaware Law”);

 

WHEREAS, the Bylaws and Delaware Law by their non-exclusive nature, permit contracts between the Corporation and its agents, officers, employees and other agents with respect to indemnification of such persons; and

 

WHEREAS, in order to induce Agent to continue to serve as [Title], the Corporation has determined and agreed to enter into this Agreement with Agent;

 

NOW, THEREFORE, in consideration of Agent’s continued service as [Title], after the date hereof, the parties hereto agree as follows:

 

AGREEMENT

 

1.                                      Services to the Corporation.  Agent will serve, at the will of the Corporation or under separate contract, if any such contract exists, as [Title] or as a director, officer or other fiduciary of an affiliate of the Corporation (including any employee benefit plan of the Corporation) faithfully and to the best of his ability so long as he  is duly elected and qualified in accordance with the provisions of the Bylaws or other applicable charter documents of the Corporation or such affiliate; provided, however, that Agent may at any time and for any reason resign from such position (subject to any contractual obligation that Agent may have assumed apart from this Agreement) and that the Corporation or any affiliate shall have no obligation under this Agreement to continue Agent in any such position.

 

2.                                      Indemnity of Agent.  The Corporation hereby agrees to hold harmless and indemnify Agent to the fullest extent authorized or permitted by the provisions of the Bylaws and Delaware Law, as the same may be amended from time to time (but, only to the extent that such amendment permits the Corporation to provide broader indemnification rights than the Bylaws or Delaware Law permitted prior to adoption of such amendment).

 

3.                                      Additional Indemnity.  In addition to and not in limitation of the indemnification otherwise provided for herein, and subject only to the exclusions set forth in Section 4 hereof, the Corporation hereby further agrees to hold harmless and indemnify Agent:

 

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(a)                                 against any and all expenses (including attorneys’ fees), witness fees, damages, judgments, fines and amounts paid in settlement and any other amounts that Agent becomes legally obligated to pay because of any claim or claims made against or by him in connection with any threatened, pending or completed action, suit or proceeding, whether civil, criminal, arbitrational, administrative or investigative (including an action by or in the right of the Corporation) to which Agent is, was or at any time becomes a party, or is threatened to be made a party, by reason of the fact that Agent is, was or at any time becomes a director, officer, employee or other agent of Corporation, or is or was serving or at any time serves at the request of the Corporation as a director, officer, employee or other agent of another corporation, partnership, joint venture, trust, employee benefit plan or other enterprise; and

 

(b)                                 otherwise to the fullest extent as may be provided to Agent by the Corporation under the non-exclusivity provisions of Delaware Law and Section 43 of the Bylaws.

 

4.                                      Limitations on Additional Indemnity.  No indemnity pursuant to Section 3 hereof shall be paid by the Corporation:

 

(a)                                 on account of any claim against Agent for an accounting of profits made from the purchase or sale by Agent of securities of the Corporation pursuant to the provisions of Section 16(b) of the Securities Exchange Act of 1934 and amendments thereto or similar provisions of any federal, state or local statutory law;

 

(b)                                 on account of Agent’s conduct that was knowingly fraudulent or deliberately dishonest or that constituted willful misconduct;

 

(c)                                  on account of Agent’s conduct that constituted a breach of Agent’s duty of loyalty to the Corporation or resulted in any personal profit or advantage to which Agent was not legally entitled;

 

(d)                                 for which payment is actually made to Agent under a valid and collectible insurance policy or under a valid and enforceable indemnity clause, bylaw or agreement, except in respect of any excess beyond payment under such insurance, clause, bylaw or agreement;

 

(e)                                  if indemnification is not lawful (and, in this respect, both the Corporation and Agent have been advised that the Securities and Exchange Commission believes that indemnification for liabilities arising under the federal securities laws is against public policy and is, therefore, unenforceable and that claims for indemnification should be submitted to appropriate courts for adjudication); or

 

(f)                                   in connection with any proceeding (or part thereof) initiated by Agent, or any proceeding by Agent against the Corporation or its directors, officers, employees or other agents, unless (i) such indemnification is expressly required to be made by law, (ii) the proceeding was authorized by the Board of Directors of the Corporation, (iii) such indemnification is provided by the Corporation, in its sole discretion, pursuant to the powers vested in the Corporation under Delaware Law, or (iv) the proceeding is initiated pursuant to Section 9 hereof.

 

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5.                                      Continuation of Indemnity.  All agreements and obligations of the Corporation contained herein shall continue during the period Agent is a director, officer, employee or other agent of the Corporation (or is or was serving at the request of the Corporation as a director, officer, employee or other agent of another corporation, partnership, joint venture, trust, employee benefit plan or other enterprise) and shall continue thereafter so long as Agent shall be subject to any possible claim or threatened, pending or completed action, suit or proceeding, whether civil, criminal, arbitrational, administrative or investigative, by reason of the fact that Agent was serving in the capacity referred to herein.

 

6.                                      Partial Indemnification.  Agent shall be entitled under this Agreement to indemnification by the Corporation for a portion of the expenses (including attorneys’ fees), witness fees, damages, judgments, fines and amounts paid in settlement and any other amounts that Agent becomes legally obligated to pay in connection with any action, suit or proceeding referred to in Section 3 hereof even if not entitled hereunder to indemnification for the total amount thereof, and the Corporation shall indemnify Agent for the portion thereof to which Agent is entitled.

 

7.                                      Notification and Defense of Claim.  Not later than thirty (30) days after receipt by Agent of notice of the commencement of any action, suit or proceeding, Agent will, if a claim in respect thereof is to be made against the Corporation under this Agreement, notify the Corporation of the commencement thereof; but the omission so to notify the Corporation will not relieve it from any liability which it may have to Agent otherwise than under this Agreement.  With respect to any such action, suit or proceeding as to which Agent notifies the Corporation of the commencement thereof:

 

(a)                                 the Corporation will be entitled to participate therein at its own expense;

 

(b)                                 except as otherwise provided below, the Corporation may, at its option and jointly with any other indemnifying party similarly notified and electing to assume such defense, assume the defense thereof, with counsel reasonably satisfactory to Agent.  After notice from the Corporation to Agent of its election to assume the defense thereof, the Corporation will not be liable to Agent under this Agreement for any legal or other expenses subsequently incurred by Agent in connection with the defense thereof except for reasonable costs of investigation or otherwise as provided below.  Agent shall have the right to employ separate counsel in such action, suit or proceeding but the fees and expenses of such counsel incurred after notice from the Corporation of its assumption of the defense thereof shall be at the expense of Agent unless (i) the employment of counsel by Agent has been authorized by the Corporation, (ii) Agent shall have reasonably concluded that there may be a conflict of interest between the Corporation and Agent in the conduct of the defense of such action or (iii) the Corporation shall not in fact have employed counsel to assume the defense of such action, in each of which case the fees and expenses of Agent’s separate counsel shall be at the expense of the Corporation.  The Corporation shall not be entitled to assume the defense of any action, suit or proceeding brought by or on behalf of the Corporation or as to which Agent shall have made the conclusion provided for in clause (ii) above; and

 

(c)                                  the Corporation shall not be liable to indemnify Agent under this Agreement for any amounts paid in settlement of any action or claim effected without the Corporation’s written consent, which shall not be unreasonably withheld.  The Corporation shall be permitted to settle any action except that it shall not settle any action or claim in any manner which would impose any penalty or limitation on Agent without Agent’s written consent, which may be given or withheld in Agent’s sole discretion.

 

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8.                                      Expenses.  The Corporation shall advance, prior to the final disposition of any proceeding, promptly following request therefor, all expenses incurred by Agent in connection with such proceeding upon receipt of an undertaking by or on behalf of Agent to repay said amounts if it shall be determined ultimately that Agent is not entitled to be indemnified under the provisions of this Agreement, the Bylaws, Delaware Law or otherwise.

 

9.                                      Enforcement.  Any right to indemnification or advances granted by this Agreement to Agent shall be enforceable by or on behalf of Agent in any court of competent jurisdiction if (i) the claim for indemnification or advances is denied, in whole or in part, or (ii) no disposition of such claim is made within ninety (90) days of request therefor.  Agent, in such enforcement action, if successful in whole or in part, shall also be entitled to be paid the expense of prosecuting his claim.  It shall be a defense to any action for which a claim for indemnification is made under Section 7 hereof (other than an action brought to enforce a claim for expenses pursuant to Section 8 hereof, provided that the required undertaking has been tendered to the Corporation) that Agent is not entitled to indemnification because of the limitations set forth in Section 4 hereof.  Neither the failure of the Corporation (including its Board of Directors or its stockholders) to have made a determination prior to the commencement of such enforcement action that indemnification of Agent is proper in the circumstances, nor an actual determination by the Corporation (including its Board of Directors or its stockholders) that such indemnification is improper shall be a defense to the action or create a presumption that Agent is not entitled to indemnification under this Agreement or otherwise.

 

10.                               Subrogation.  In the event of payment under this Agreement, the Corporation shall be subrogated to the extent of such payment to all of the rights of recovery of Agent, who shall execute all documents required and shall do all acts that may be necessary to secure such rights and to enable the Corporation effectively to bring suit to enforce such rights.

 

11.                               Non-Exclusivity of Rights.  The rights conferred on Agent by this Agreement shall not be exclusive of any other right which Agent may have or hereafter acquire under any statute, provision of the Corporation’s Certificate of Incorporation or Bylaws, agreement, vote of stockholders or directors, or otherwise, both as to action in his official capacity and as to action in another capacity while holding office.

 

12.                               Survival of Rights.

 

(a)                                 The rights conferred on Agent by this Agreement shall continue after Agent has ceased to be a director, officer, employee or other agent of the Corporation or to serve at the request of the Corporation as a director, officer, employee or other agent of another corporation, partnership, joint venture, trust, employee benefit plan or other enterprise and shall inure to the benefit of Agent’s heirs, executors and administrators.

 

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(b)                                 The Corporation shall require any successor (whether direct or indirect, by purchase, merger, consolidation or otherwise) to all or substantially all of the business or assets of the Corporation, expressly to assume and agree to perform this Agreement in the same manner and to the same extent that the Corporation would be required to perform if no such succession had taken place.

 

13.                               Separability.  Each of the provisions of this Agreement is a separate and distinct agreement and independent of the others, so that if any provision hereof shall be held to be invalid for any reason, such invalidity or unenforceability shall not affect the validity or enforceability of the other provisions hereof.  Furthermore, if this Agreement shall be invalidated in its entirety on any ground, then the Corporation shall nevertheless indemnify Agent to the fullest extent provided by the Bylaws, Delaware Law or any other applicable law.

 

14.                               Governing Law.  This Agreement shall be interpreted and enforced in accordance with the laws of the State of Delaware.

 

15.                               Amendment and Termination.  No amendment, modification, termination or cancellation of this Agreement shall be effective unless in writing signed by both parties hereto.

 

16.                               Identical Counterparts.  This Agreement may be executed in one or more counterparts, each of which shall for all purposes be deemed to be an original but all of which together shall constitute but one and the same Agreement.  Only one such counterpart need be produced to evidence the existence of this Agreement.

 

17.                               Headings.  The headings of the sections of this Agreement are inserted for convenience only and shall not be deemed to constitute part of this Agreement or to affect the construction hereof.

 

18.                               Notices.  All notices, requests, demands and other communications hereunder shall be in writing and shall be deemed to have been duly given (i) upon delivery if delivered by hand to the party to whom such communication was directed or (ii) upon the third business day after the date on which such communication was mailed if mailed by certified or registered mail with postage prepaid:

 

(a)                                 If to Agent, at the address indicated on the signature page hereof.

 

(b)                                 If to the Corporation, to

Isis Pharmaceuticals, Inc.

2855 Gazelle Court

Carlsbad, CA  92010

Attention:  Chief Operating Officer

 

or to such other address as may have been furnished to Agent by the Corporation.

 

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IN WITNESS WHEREOF, the parties hereto have executed this Agreement on and as of the day and year first above written.

 

 

	
 
    	
ISIS   PHARMACEUTICALS, INC.
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
By:
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
Title:
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
AGENT
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
(signature)
    
	
 
    	
 
    
	
 
    	
Agent   Print Name and Address:
    

 

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Schedule of Executive Officers and

Directors with Indemnity Agreements

 

Stanley T. Crooke, M.D., Ph.D., Chairman, Chief Executive Officer and President

B. Lynne Parshall, J.D., Director, Chief Operating Officer, Secretary, and Director

C. Frank Bennett, Ph.D., Senior Vice President, Antisense Research

Richard S. Geary, Ph.D., Senior Vice President, Development

Elizabeth L. Hougen, Senior Vice President, Finance and Chief Financial Officer

Brett P. Monia, Ph.D., Senior Vice President, Drug Discovery and Corporate Development

Patrick R. O’Neil, Esq., Senior Vice President, Legal and General Counsel

Spencer R. Berthelsen, M.D., Director

Joseph Klein, III, Director

Frederick T. Muto, Esq., Director

Joseph H. Wender, DirectorEXHIBIT 10.44

 

CONFIDENTIAL

EXECUTION COPY

 

CONFIDENTIAL TREATMENT REQUESTED

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

 

AMENDMENT #2 TO RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT

 

This AMENDMENT #2 TO THE RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT (this “Amendment”) is entered into and made effective as of the 30th day of October, 2012 (the “Amendment 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 Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN, England (“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”);

 

WHEREAS, Isis and GSK desire to amend the Agreement to more rapidly Develop the drug, ISIS-TTRRx (ISIS 420915), under the Rare Disease Program focused on the Collaboration Target, Transthyretin (the “TTR Program”), which may enable ISIS-TTRRx to reach registration earlier than originally estimated; and

 

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 — Drug Development Activities.

 

a.                                      Phase 2 PoC Trial. The Parties have mutually agreed to a clinical study design for the Phase 2 PoC Trial (as defined hereinafter) for the TTR Program that is reflected in the TTR Development Plan and further described in the other TTR Registration-Directed Program Documents.  The Phase 2 PoC Trial for the TTR Program is intended to demonstrate therapeutic benefit in patients with familial amyloid polyneuropathy (FAP).  The Phase 2 PoC Trial for the TTR Program and the TTR Registration-Directed Program Documents are intended to support registration filings and Approval of ISIS-TTRRx on a global basis. The Parties will mutually agree on any material changes to the TTR Registration-Directed Program Documents in accordance with Section 7 of this Amendment.

 

b.                                      First Interim Analysis; GSK’s Evaluation.  In accordance with the DSMB Charter, the Parties expect the Independent Statistician will perform the First

 

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Interim Analysis and provide the data from such First Interim Analysis (the “Interim Data Package”) to the DSMB and to each Partner Firewalled Staff.  The Parties agree there will be [***] Partner Firewalled Staff members. [***]

 

c.                                       Notice of GSK’s Decision Whether to Terminate its Option for the TTR Program.

 

i.                                          GSK Delivers the TTR Termination Notice to Isis.  GSK will notify Isis within [***] days after the date the Partner Firewalled Staff receive the Interim Data Package if GSK desires to terminate its Option to the TTR Program. If GSK provides written notice to Isis during such [***] period that GSK is terminating its Option to the TTR Program under the Agreement (a “TTR Termination Notice”), then (A) GSK will have no further rights or obligations with regard to the TTR Program; (B) GSK’s Option to the TTR Program will terminate; and (C) subject to Section 9 of this Amendment and the terms and conditions of the Agreement (as amended by this Amendment), Isis will be free to develop and commercialize any Compounds that were included in the TTR Program on its own or with a Third Party.  For clarity, GSK shall have the right under this Section 1.c.i to terminate its Option to the TTR Program irrespective of the outcome of the First Interim Analysis. If Isis notifies GSK within [***] days after Isis’ receipt of the TTR Termination Notice that [***].  For clarity, GSK has no obligation to [***].

 

ii.                                       GSK Continues TTR Program. If GSK does not provide a TTR Termination Notice to Isis during such [***]day period, Isis will continue the Phase 2 PoC Trial for the TTR Program, and GSK will retain its Option to the TTR Program under the Agreement, as modified by this Amendment. Isis will continue enrolling additional patients to complete the Phase 2 PoC Trial in accordance with the TTR Registration-Directed Program Documents and this Amendment.

 

d.                                      Second Interim Analysis (Sample Re-Sizing Analysis) — DSMB Meeting. If the TTR Program is not terminated pursuant to Section 1c.i. of this Amendment, then, in accordance with the DSMB Charter, the Parties expect the Independent Statistician and the DSMB to perform the Second Interim Analysis and, based on such results the DSMB will notify the Sponsor Primary Contact and the Partner Firewalled Staff members whether or not the DSMB recommends increasing the patient sample size and the number of patients to be added, if any, for the Phase 2 PoC Trial in accordance with the DSMB Charter.

 

i.                                          Adding [***] Patients.  If the DSMB recommends that [***] patients be added to the Phase 2 PoC Trial, then Isis will add such number of patients to the Phase 2 PoC Trial and GSK will fund such additional patients by paying Isis $[***] per such additional patient.

 

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ii.                                       Adding [***] Patients.  If the DSMB recommends that [***] patients (each, a “[***]”) be added to the Phase 2 PoC Trial, then, Isis will provide GSK written notice (a “[***] Notice”) of the number of additional patients (if any) Isis intends to add to the Phase 2 PoC Trial within [***] Business days after the DSMB provides such recommendation to the Parties, and either:

 

1.                                      If the number of additional patients Isis specifies in the [***] Notice is the [***], then Isis will add such number of additional patients to the Phase 2 PoC Trial, and GSK may elect to fund such additional patients at the rate of $[***] per patient by notifying Isis thereof within [***] Business days of GSK’s receipt of the [***] Notice.

 

2.                                      If the number of additional patients Isis specifies in the [***] Notice is (A) [***] or (B) [***], then in either case GSK and Isis will as soon as practicable discuss in good faith the number of additional patients to add to the Phase 2 PoC Trial with the goal of preserving the value of such study.  If, within [***] Business Days after the discussion between the Parties, GSK agrees to fund the number of additional patients specified in the [***] Notice, or such number of patients agreed to by the Parties, then Isis will add the number of patients GSK has agreed to fund to the Phase 2 PoC Trial and GSK will fund such additional patients at the rate of $[***] per patient.

 

If GSK does not agree to fund the additional patients under (y) part 1 of this Section 1.d.ii within [***] Business Days after GSK’s receipt of the [***] Notice, or (z) part 2 of this Section 1.d.ii within [***] Business Days after such discussion between the Parties, then Isis will add the number of patients specified in the [***] Notice to the Phase 2 PoC Trial and, GSK will retain its Option to the TTR Program; provided, however, that [***].

 

Isis will not add additional patients to the Phase 2 PoC Trial that exceed either (i) the [***] or (ii) [***], whichever is [***], without GSK’s written consent.

 

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2.                                      TTR Program — Drug Development Activities and Costs.

 

a.                                      Development Costs Paid by Isis.

 

i.                                          Before Option Exercise. Until GSK exercises its Option for the TTR Program, Isis will be responsible for Isis’ activities under the TTR Registration-Directed Program Documents and all costs and expenses associated therewith except as otherwise provided under Section 1.d. (Second Interim Analysis (Sample Re-Sizing Analysis) — DSMB Meeting), Section 2.b. (Development Costs Paid by GSK), Section 3. (Supply Chain Strategy) or Section 4.d. (Compensation for Activities Performed by Isis) of this Amendment.

 

ii.                                       Contract Clinical Trial Services by GSK in [***] and/or [***]. If the Parties mutually agree to include patients in [***] and/or [***] in the Phase 2 PoC Trial, Isis will engage GSK or GSK’s Affiliates in [***] and/or [***] (as applicable) to provide contract clinical study services under a clinical study services agreement with customary terms and conditions, including, without limitation, [***]. In exchange, Isis will pay GSK or GSK’s Affiliate a fee for such services at a rate of $[***] per enrolled patient that completes i) the [***] or ii) the [***], as defined in the Protocol, and Isis will make such payment within sixty (60) days after Isis’ receipt of an invoice from GSK or GSK’s Affiliate.

 

iii.                                    [***] Services by GSK. If the Parties mutually agree to engage GSK or GSK’s Affiliates to perform [***] services for the Phase 2 PoC Trial, Isis will engage GSK or GSK’s Affiliates to perform [***] services for the Phase 2 PoC Trial, with any mutually agreed fees (but in no event will such fees be [***]), and Isis will make such payment within sixty (60) after Isis’ receipt of an invoice from GSK or GSK’s Affiliate.

 

b.                                      Development Costs Paid by GSK.

 

i.                                          Before Option Exercise.

 

1.                                      Additional Costs. GSK will be responsible for paying the Additional Costs resulting from Approved Changes in the manner as agreed to by the Parties pursuant to Section 7.b. On a quarterly basis, Isis will deliver to GSK an invoice for such portion of the Additional Costs that are allocated for the activities for the coming quarter [***], which GSK will pay each such invoice within [***] days after GSK’s receipt.

 

2.                                      Costs Associated with Additional Patients.  With respect to the additional patients that GSK is obligated to fund pursuant to Section 1.d.i or agrees to fund pursuant to Section 1.d.ii.1 or Section 1.d.ii.2, GSK will fund each such additional patient at

 

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$[***] per patient, and will remit payment of such amount to Isis as follows:

 

i.              $[***] for each such additional patient [***] within [***] days after GSK’s receipt of an invoice from Isis; and

 

ii.             When at least [***] of such additional patients are enrolled in the Phase 2 PoC Trial, the remaining $[***] for each such additional patient [***] within [***] days after GSK’s receipt of an invoice from Isis.

 

ii.                                       After Option Exercise.

 

1.                                      Generally. Without limiting the Agreement, after GSK exercises the Option for the TTR Program, GSK will be solely responsible for and have sole decision making authority over all Development and Commercialization activities, and will be solely responsible for all costs and expenses associated therewith, with respect to the Development, Manufacture and Commercialization of Licensed Compounds and related Licensed Products, including, but not limited to, the costs and expenses of completing any uncompleted activities under the TTR Registration-Directed Program Documents, but excluding [***].

 

2.                                      Technology Transfer; Transition Services. Without limiting the Agreement, after GSK exercises the Option for the TTR Program, Isis will transfer all Licensed Know-how (including all regulatory approvals and regulatory materials and clinical and non-clinical studies relating to the TTR Program) to GSK and provide transition services to GSK in accordance with Section 4.2.1 of the Agreement and additional services upon GSK’s request in accordance with Section 4.2.2 of the Agreement. The Parties acknowledge that, due to the nature of this Amendment, certain transition services of the transition services provided in accordance with Section 4.2.1 or 4.2.2 of the Agreement may need to be initiated prior to Option exercise, and Isis agrees to use its Commercially Reasonable Efforts to assist with such transition services as requested by GSK, taking into consideration the need for an efficient transition to continue successful Development and Commercialization of ISIS-TTRRx.

 

3.                                      Transfer of the Sponsorship of the OLE Study.  Without limiting the Agreement, after GSK exercises the Option for the TTR Program, Isis will transfer the sponsorship of the OLE Study to GSK and at GSK’s option and expense, all of the responsibilities thereunder to GSK.  If GSK opts not to have the responsibilities thereunder transferred from Isis to GSK, GSK shall promptly enter

 

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into a services agreement, pursuant to which GSK will engage Isis at GSK’s expense to continue its activities to oversee and manage the OLE Study on terms and conditions agreed to by both Parties.

 

3.                                      Supply Chain Strategy.

 

a.                                      Mutually Agreed Strategy. Subject to this Section 3.a of this Amendment, Isis will be responsible for manufacturing (or having manufactured) a sufficient quantity of API and finished product to complete the Phase 2 PoC Trial and the Phase 2 PoC Trial Support Activities.  By the [***] following the Amendment Date, the Parties will form a CMC sub-team (the “CMC Sub-Team”) pursuant to Section 6.a, which will discuss and, by [***] agree upon, a high level supply chain strategy to supply API and finished product for Commercialization of Licensed Products (“Commercial Supplies”), and GSK will have the final decision-making authority regarding the strategy and steps towards development of Commercial Supplies as well as clinical supplies after GSK’s exercise of the Option.

 

b.                                      Isis May Supply API for Initial Commercialization.

 

i.                                          Isis May Supply API to GSK for Initial Commercialization. In support of obtaining Approval and Commercialization of Licensed Products, the Parties may by separate agreement mutually agree that GSK will contract with Isis for Isis to manufacture and supply API for commercial launch of Licensed Products and for a post-launch Commercialization period of up to [***] (unless the Parties otherwise agree to a longer period), pursuant to a commercial supply agreement (the “Isis-GSK Commercial API Supply Agreement”).  In addition, GSK and Isis may enter into a mutually agreed services agreement (the “Services Agreement”) pursuant to which Isis will perform validation work, manufacture and supply validation lots (if not included under the Isis API Commercial Supply Agreement) and registration stability lots to GSK and prepare the draft of the chemistry, manufacturing and controls (“CMC”) section for the NDA, MAA or other marketing authorization applications.

 

ii.                                       API Manufacturing Technology Transfer. The Isis-GSK Commercial API Supply Agreement will provide that, no later than [***] prior to the [***], Isis will, in accordance with and subject to the general technology transfer principles described in Section 4.2.1 of the Agreement, in accordance with [***] conduct a technology transfer to GSK (or GSK’s designated Third Party supplier) of all technology, information and data related to Isis’ manufacturing and supply of the API, and Isis will continue to supply API to GSK for [***] to enable GSK to (i) identify and contract with a suitable Third Party API manufacturer or (ii) transfer the manufacture of API to a qualified GSK manufacturing site. Such API manufacturing technology transfer will be initiated earlier if GSK desires

 

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to establish a back-up manufacturing facility or if Isis fails to supply API as required under the Isis-GSK Commercial API Supply Agreement.

 

c.                                       Manufacturing of Finished Product by GSK.

 

i.                                          GSK to Manufacture Finished Product. Subject to the terms of this Section 3.c.i and the terms of the Agreement (as amended by this Amendment), GSK will manufacture and supply finished product and corresponding placebo (new supply) for the Phase 2 PoC Trial and/or the Phase 2 PoC Trial Support Activities. In addition, the Parties acknowledge that, subject to the terms of this Section 3.c.i and the terms of the Agreement (as amended by this Amendment), GSK will manufacture or have manufactured finished product for Commercialization.

 

ii.                                       GSK-Isis Finished Product Supply Agreement for Clinical Studies. The terms for any such transfer and supply of finished product and corresponding placebo (new supply) by GSK for the Phase 2 PoC Trial and/or the Phase 2 PoC Trial Support Activities will be pursuant to mutually agreed supply and quality agreement(s) (the “GSK-Isis Finished Product Supply Agreement for Clinical Studies”), with GSK to be compensated for its manufacture of any finished product (or placebo) used in the Phase 2 PoC Trial in an amount equal to $[***] per finished product/placebo batch fill (with the batch size to be mutually agreed). The GSK-Isis Finished Product Supply Agreement for Clinical Studies will include the manufacturing technology transfer provisions set forth in Section 3ciii below, and will also contain, but not be limited to, the terms only for supply of finished product (or placebo) for the Phase 2 PoC Trial and Phase 2 PoC Trial Support Activities.  The prices for GSK to supply finished product (or placebo) other than for the Phase 2 PoC Trial and Phase 2 PoC Trial Support Activities will be [***].

 

iii.                                    Finished Product Manufacturing Technology Transfer.

 

1.                                      Initial Finished Product Manufacturing Technology Transfer from Isis to GSK.  To facilitate GSK in manufacturing the finished product for the Phase 2 PoC Trial, the Phase 2 PoC Trial Support Activities, and Commercialization, the Parties will collaborate to facilitate a technology transfer to a finished product manufacturing site identified by GSK in support thereof. Isis will be compensated by GSK for Isis’ technology transfer efforts based on a mutually agreed plan, including, the cost of Isis’ time incurred in performing such work at [***] plus any reasonable out-of-pocket expenses incurred by Isis in performing such work. Isis will invoice GSK for any such work and costs and GSK will pay the invoices submitted within [***] days after receipt of the applicable invoice by GSK.

 

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2.                                      Manufacturing Technology Transfer from GSK to Isis at Termination. If the Agreement terminates or the Option for the TTR Program is terminated or expires unexercised, Isis may request GSK to conduct a technology transfer to Isis (or Isis’ designated Third Party supplier) of any technology, information and data reasonably related to GSK’s manufacturing and supply of such finished product, and if so requested, GSK will, [***], conduct such a technology transfer and GSK will continue to (i) provide reasonable support and cooperation with Isis’ regulatory filings and interactions with Regulatory Authorities related to GSK’s finished product manufacturing (including any required inspections), and (ii) supply finished product to Isis, [***] to enable Isis to identify and contract with a suitable Third Party finished product manufacturer.  Notwithstanding, any termination or expiration of the Option, Isis agrees to include GSK among the third party contract manufactures being evaluated for the manufacture and supply of finished product, whether for clinical trials or Commercialization.

 

4.                                      Collaboration in Regulatory Activities.

 

a.                                      Regulatory Plan.  Isis and GSK will form a regulatory subteam (the “Regulatory Sub-Team”) pursuant to Section 6.a, which will produce a high-level outline, [***], which outline to be mutually agreed no later than [***].  Following the First Interim Analysis, the Regulatory Sub-Team, in collaboration with other sub-teams formed hereunder, will mutually develop and agree to a detailed plan for coordination and preparation of the NDA and MAA for ISIS-TTRRx (including establishing responsibilities for provision of all sections of the electronic common technical document (“eCTD”) modules, authorship, plan activity timelines and any associated costs and expenses, including any work GSK would like Isis to perform) to ensure a smooth transition to GSK, accelerate eCTD completion and facilitate rapid NDA, MAA and JNDA filings. Once the Parties mutually agree upon such a plan, each Party will use Commercially Reasonable Efforts to execute their respective tasks and responsibilities under such plan in the time frames set forth in such plan.

 

b.                                      GSK’s Participation in Regulatory Activities.  With respect to the TTR Program, prior to Option exercise, Isis will keep GSK informed about its regulatory activities and communications it has with the Regulatory Authorities. Isis will provide as much advance notice as possible to GSK and [***] after its receipt of the notice from a Regulatory Authority  about its meetings or conference calls it will have with such Regulatory Authority, and provide GSK with a reasonable opportunity to participate as an observer in the meeting at GSK’s expense to provide Isis with information and suggestions. In addition, Isis will provide GSK with full access to all available documentation needed by GSK in preparing NDA, MAA and other marketing authorization applications, in addition to other

 

8

 

regulatory activities as well as GSK’s preparation for interacting with Regulatory Authorities.

 

c.                                       Isis’ Participation in Regulatory Activities.  After Option exercise, GSK will provide advance notice to Isis promptly after its receipt of a notice from a Regulatory Authority  about any meetings or conference calls GSK will have with such Regulatory Authority and, at GSK’s discretion, will provide Isis with a reasonable opportunity to participate as an observer in the meeting at Isis’ expense to provide GSK with information and suggestions. GSK will inform Isis about its regulatory activities in a summary format and material communications it has with the Regulatory Authorities that may affect the TTR Program or other Collaboration Programs.

 

d.                                      Compensation for Activities Performed by Isis.  In accordance with Section 4.2.2 of the Agreement, GSK will pay Isis for Isis’ time in performing Isis’ regulatory plan activities described in Section 4.a of this Amendment at [***]. GSK may request assistance from Isis prior to Option exercise, and Isis will consider any such request in good faith.

 

5.                                      Option.  Following GSK’s receipt of the PoC Trial Completion Notice (including the Phase 2 PoC Data Package as defined in this Amendment) for the TTR Program, GSK will provide written notice to Isis of its decision whether or not to exercise its Option to the TTR Program under Section 3.1 of the Agreement as soon as possible, but in any case, on or before 5:00 p.m. (Eastern time) on the [***] ([***]) day following GSK’s receipt of the PoC Trial Completion Notice (the “Option Deadline”). If GSK does not provide written notice to Isis of GSK’s determination to license the TTR Program before the Option Deadline, then GSK’s Option to the TTR Program will expire and, subject to Section 9 of this Amendment and the terms of the Agreement (as amended by this Amendment), Isis will be free to Develop and Commercialize any Compounds that were included in the TTR Program on its own or with a Third Party.

 

9

 

6.                                      TTR Steering Committee.

 

a.                                      Formation of the TTR Steering Committee. Within [***] after the Amendment Date, with respect to the TTR Program, the Parties will establish a TTR steering committee (“TTR Steering Committee”) that will be separate and independent from the JSC, and which will be responsible for the coordination and management of activities to develop the regulatory strategy and CMC strategy through Option exercise to enable a smooth transition of such activities. The TTR Steering Committee will consist of three representatives of Isis and three representatives of GSK. The TTR Steering Committee may elect to create sub-teams designated to address the following areas: (i) regulatory; (ii) CMC; and (iii) clinical, with representatives responsible for ensuring that activities occur as set forth in this Amendment and the TTR Registration-Directed Program Documents. The TTR Steering Committee will operate in accordance with the same operating procedures for the JSC as set forth in Section 1.3.1 of the Agreement.

 

b.                                      Roles of the TTR Steering Committee and Sub-Teams Formed Thereunder. Subject to Section 6.c of this Amendment and solely in connection with the TTR Program, the TTR Steering Committee (or any sub-teams formed by the TTR Steering Committee) will perform the following functions, some or all of which may be addressed directly at any given meeting of the TTR Steering Committee or a sub-team:

 

i.                                          review the TTR Registration-Directed Program Documents from time to time and prepare Material Amendments, if any, to the TTR Registration-Directed Program Documents;

 

ii.                                       develop CMC strategy and manage development activities, including process development, formulation development, quality control, stability tests, scale up, etc.;

 

iii.                                    manage the manufacture and supply of API and/or finished product for Clinical Studies;

 

iv.                                   review and oversee the clinical monitoring program and the statistical analysis plan (including establishing a mutually agreed process for GSK to participate in in-stream safety data review with Isis);

 

v.                                      develop regulatory strategy and coordinate, review and oversee regulatory activities conducted under the TTR Registration-Directed Program Documents;

 

vi.                                   facilitate sharing of data and information between the Parties’ regulatory teams to ensure each Party’s access to all data;

 

vii.                                coordinate meetings and other interactions (including written correspondence) with Regulatory Authorities;

 

10

 

 

viii.                             develop  a transition plan prior to GSK’s exercise of the Option, including coordinating the transfer of manufacturing technology and delivery of regulatory materials, and execute such plan; and

 

ix.                                   such other review and advisory responsibilities as may be assigned to the TTR Steering Committee pursuant to this Amendment or as may be mutually agreed upon in writing by the Parties from time to time.

 

c.                                       Decision Making. The Parties will conduct the TTR Program in accordance with the TTR Registration-Directed Program Documents, giving due consideration to the recommendations and advice of the TTR Steering Committee. Isis will have the final decision-making authority regarding [***].

 

d.                                      Briefing the TTR Steering Committee. At each regularly scheduled meeting of the TTR Steering Committee, Isis will provide to the TTR Steering Committee [***].

 

e.                                       Term of TTR Steering Committee. The TTR Steering Committee (and any of its sub-teams and working groups) under this Amendment will cease to exist upon the earlier of exercise, termination or expiration of the Option with respect to the TTR Program.

 

f.                                        Meeting Coordination. The TTR Steering Committee will meet at least once per quarter in person or via video teleconference or conference and more frequently whenever necessary and will meet in person at least twice a year. Isis and GSK will use commercially reasonable efforts to schedule meetings of the JSC and TTR Steering Committee to take place at the same location and on the same dates to maximize the use of each Party’s time, increase information sharing efficiencies and reduce the cost of additional travel, lodging and related expenses.

 

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

 

a.                                      Overview.  As of the Amendment Date, the Parties have agreed to the TTR Development Plan (which is attached hereto as ATTACHMENT 1), as well as the SPA, the Protocol and the DSMB Charter, all of which have been delivered to each Party under separate cover.

 

b.                                      Material Amendment Process. No material amendment to any TTR 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 feedback from a Regulatory Authority, either Party requests a change to the Phase 2 PoC Trial or any TTR Registration-Directed Program Document that requires the Parties to make a Material Amendment to a TTR 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  (including any associated Additional Costs and the payment schedule thereof) to such TTR Registration-Directed Program Document within [***] days of receiving such proposed change from such Regulatory Authority or a Party. If 

 

11

 

the Parties mutually agree to such a Material Amendment (including any associated Additional Costs and the payment schedule thereof), Isis will continue to perform the Phase 2 PoC Trial in accordance with such amended TTR 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 Registration-Directed Program Document (including any associated Additional Costs and the payment schedule thereof) 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 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:

 

i.      if the dispute arose [***], then [***]; or

 

ii.   if the dispute arose [***], then [***].

 

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

 

8.                                      Financial Provisions. The following financial provisions will apply solely to the TTR Program:

 

a.                                      Upfront Fee.  GSK will pay Isis $2,500,000 within [***] days of GSK’s receipt of the invoice from Isis following the Amendment Date.

 

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

 

12

 

TABLE X

 

	
Development Milestone Events for a Compound
    	
 
    	
Milestone Payment
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Initiation of the Phase 2 PoC Trial  
    	
 
    	
$
    	
7,500,000
    	
 
    
	
[***]  
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]  
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]  
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
[***]
    	
 
    	
$
    	
[***]
    	
 
    
	
Total   Development Milestone Payments for the TTR Program 
    	
 
    	
$
    	
[***]
    	
 
    

 

“Dosing” or “Dosed” means, with respect to the above milestone events, administration of the first dose of ISIS-TTRRx or placebo to the applicable patient in the Phase 2 PoC Trial in accordance with the TTR Registration-Directed Program Documents.

 

Notwithstanding Section 5.8.2 of the Agreement, Isis will send GSK a written notice promptly following the date when the “Initiation of the Phase 2 PoC Trial” Milestone Event in TABLE X is achieved, and the $7,500,000 milestone payment will be due within [***] Business Days of GSK’s receipt of the invoice.

 

c.                                       TTR Program Option Exercise Fee. Upon the exercise by GSK of the Option for the TTR Program in accordance with the Agreement (as amended by this Amendment), 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 $[***] ([***]), within [***] days after receipt by GSK of an invoice sent from Isis on or after such Option exercise becomes effective under the Agreement (as amended by this Amendment).

 

d.                                      Milestone Payments for First Achievement of Sales Milestone Event. Solely with respect to a Licensed Product under the TTR Program, TABLE 4 set forth in 

 

13

 

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 Y below:

 

TABLE Y

 

	
Sales Milestones for Licensed Products in the TTR Program
    	
 
    	
Milestone Payment
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
$[***] in worldwide Annual Net Sales  
    	
 
    	
$
    	
 
    	
[***]
    	
 
    
	
$[***] in worldwide Annual Net Sales  
    	
 
    	
$
    	
 
    	
[***]
    	
 
    
	
$[***] in worldwide Annual Net Sales  
    	
 
    	
$
    	
 
    	
[***]
    	
 
    
	
$[***] in   worldwide Annual Net Sales  
    	
 
    	
$
    	
 
    	
[***]
    	
 
    
	
$[***] in   worldwide Annual Net Sales  
    	
 
    	
$
    	
 
    	
[***]
    	
 
    
	
Total   Sales Milestone Payments for the TTR Program 
    	
 
    	
$
    	
 
    	
[***]
    	
 
    

 

9.                                      TTR Program Reverse Royalties.  Solely with respect to any Discontinued Products for which GSK has [***], 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 Z below:

 

TABLE Z

 

	
Development/Regulatory Status of Discontinued
   Product at time of reversion under this
   Agreement
    	
 
    	
Applicable Royalty Rate on worldwide
   Annual Net Sales of Discontinued
   Product
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
[***]
    	
%
    
	
[***]  
    	
 
    	
[***]
    	
%
    
	
[***]  
    	
 
    	
[***]
    	
%
    
	
[***]  
    	
 
    	
[***]
    	
%
    

 

10.                               No Impact on Other Collaboration Programs. Except as otherwise expressly amended by this Amendment, the Agreement remains in full force and effect in accordance with its terms. For the avoidance of doubt, this Amendment is solely intended to modify certain 

 

14

 

terms of the Agreement regarding the TTR Program, and does not amend the Agreement in any way with respect to the other Collaboration Programs.

 

11.                               Termination for a Safety Concern.

 

a.                                      Required by Regulatory Authorities or Mutually Agreed.  If a Safety Concern arises that causes (i) the DSMB or any Regulatory Authority to require that the Phase 2 PoC Trial be placed on clinical hold or terminated or (ii) the Parties to agree that the Phase 2 PoC Trial should be terminated, then in each case termination of the Phase 2 PoC Trial should be initiated within [***] ([***]) days after such request or agreement and GSK may terminate its Option to the TTR Program with thirty (30) days advance notice.

 

b.                                      Not Required by Regulatory Authorities or Mutually Agreed.  If a Safety Concern arises that causes the DSMB, any Regulatory Authority, or GSK’s Global Safety Board to recommend (but not require) that the Phase 2 PoC Trial be placed on clinical hold or terminated and the Parties cannot agree on whether the Phase 2 PoC Trial should be placed on clinical hold or terminated, the Parties will promptly (but no later than fifteen (15) days after such Safety Concern arises) meet and confer to discuss such Safety Concern and use good faith efforts to resolve such Safety Concern in a manner that permits continuation of the Phase 2 PoC Trial. If, after such good faith discussions (including discussions with the DSMB), such Safety Concern cannot be resolved to GSK’s satisfaction,  GSK will have the right to terminate its Option to the TTR Program by providing Isis written notice, which termination will become effective on the thirtieth (30th) day following Isis’ receipt of such termination notice.

 

c.                                       Consequences of Termination. If GSK terminates its Option to the TTR Program under Section 11.a or Section 11.b of this Amendment, (i) GSK will have no obligation to [***], (ii) Isis will have no obligation to [***] and (iii) GSK will [***] if Isis directs, by written 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 within thirty (30) days after GSK’s termination notice.

 

12.                               Restriction on GSK’s Right to Terminate for Convenience. Except in accordance with Section 1.c.i, Section 11.a or Section 11.b of this 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) until GSK’s Option to the TTR Program expires.

 

13.                               Definitions.  Capitalized terms not otherwise defined herein will have the meanings given in the Agreement. For purposes of this Amendment, the following capitalized terms will have the following meanings:

 

a.                                      “[***]” has the meaning set forth in Section 1.d of this Amendment.

 

b.                                      “Additional Costs” means, [***].

 

15

 

c.                                       “Approved Changes” means any changes (including duration of dosing, additional studies, additional endpoints, additional analysis, etc.) to the TTR Registration-Directed Program Documents (including any Material Amendments) that are requested by GSK or required by a Regulatory Authority and mutually agreed by GSK and Isis.

 

d.                                      “CMC” has the meaning set forth in Section 3.b.i of this Amendment.

 

e.                                       “CMC Sub-Team” has the meaning set forth in Section 3.a of this Amendment.

 

f.                                        “Commercial Supplies” has the meaning set forth in Section 3.a of this Amendment.

 

g.                                      “Dosing” has the meaning set forth in Section 8.b of this Amendment.

 

h.                                      “DSMB” means the Data and Safety Monitoring Board for the Phase 2 PoC Trial for the TTR Program.

 

i.                                         “DSMB Charter” means the charter that governs the activities and duties of the DSMB and its members which was submitted to the FDA on [***], as may be amended from time to time pursuant to Section 7 of this Amendment.

 

j.                                         “eCTD” has the meaning set forth in Section 4.a of this Amendment.

 

k.                                      “First Interim Analysis” means the first interim analysis described in the DSMB Charter.

 

l.                                         “GSK-Isis Finished Product Supply Agreement for Clinical Studies” has the meaning set forth in Section 3.c.ii of this Amendment.

 

m.                                  “Independent Statistician” has the meaning ascribed to it in the DSMB Charter.

 

n.                                      “Initiation of the OLE Study” means the date the first human patient enrolled in the Phase 2 PoC Trial for the TTR Program reaches the [***] time point in such Phase 2 PoC Trial.

 

o.                                      “Initiation of the Phase 2 PoC Trial” means [***].

 

p.                                      “Interim Data Package” has the meaning set forth in Section 1.b of this Amendment.

 

q.                                      “ISIS-TTRRx” means the Compound known as ISIS 420915.

 

r.                                       “Isis-GSK Commercial API Supply Agreement” has the meaning set forth in Section 3.b.i of this Amendment.

 

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

 

16

 

t.                                         “OLE Study” means the open label extension study of ISIS-TTRRx described in the TTR Development Plan.

 

u.                                      “Option Deadline” has the meaning set forth in Section 5 of this Amendment.

 

v.                                      “Partner Firewalled Staff”  has the meaning set forth in the DSMB Charter.

 

w.                                    “Phase 2 PoC Data Package” means, with respect to ISIS-TTRRx, (i) [***], (ii) [***], (iii) [***], (iv) [***], (v) copies of all filings submitted to Regulatory Authorities regarding ISIS-TTRRx, (vi) [***], and (vii) [***] together with the foregoing information listed in clause (i) through (vi), to the extent available, with respect to the [***] of ISIS-TTRRx.

 

x.                                      “Phase 2 PoC Trial” means, with respect to ISIS-TTRRx, the Phase 2/3, multicenter, double-blind, randomized, stratified, placebo-controlled study of ISIS-TTRRx in Stage 1 and Stage 2 FAP patients with [***], as described in the TTR Registration-Directed Program Documents that is intended to be used for the global registration of ISIS-TTRRx.

 

y.                                      “Phase 2 PoC Trial Support Activities” means the [***] and the [***] identified under the “Phase 2 PoC Trial Support Activities” section of the TTR Development Plan.

 

z.                                       “Protocol” means the protocol No. ISIS 420915-CS2 entitled “A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy” for the conduct of the Phase 2 PoC Trial which was submitted to the FDA on [***], as may be amended from time to time pursuant to Section 7 of this Amendment.

 

aa.                               “Regulatory Sub-Team” has the meaning set forth in Section 4.a of this Amendment.

 

bb.                               “Reviewing Entity” means an institutional review board (IRB), research ethics board (REB), European ethical committee (EEC), or equivalent appropriate governmental ethical reviewing entity responsible for approving an entity to participate in the Phase 2 PoC Trial as a clinical site.

 

cc.                                 “Safety Concern” means [***].

 

dd.                               “Second Interim Analysis” means the second interim analysis described in the DSMB Charter.

 

ee.                                 “Services Agreement” has the meaning set forth in Section 3.b.i of this Amendment.

 

ff.                                   “SPA”  or “Special Protocol Assessment” means the request for special protocol assessment for the Phase 2 PoC Trial which was submitted by Isis to FDA.

 

17

 

gg.                               “Sponsor Primary Contact”  has the meaning set forth in the DSMB Charter.

 

hh.                               “TTR 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.

 

ii.                                     “TTR Registration-Directed Program Documents” means the TTR Development Plan, the SPA, the Protocol and the DSMB Charter.

 

jj.                                     “TTR Steering Committee” has the meaning set forth in Section 6.a of this Amendment.

 

kk.                               “TTR Termination Notice” has the meaning set forth in Section 1.c.i of this Amendment.

 

* - * - * - *

 

[Signature page follows]

 

18

 

IN WITNESS WHEREOF, the Parties have caused this Amendment to be executed by their duly authorized representatives as of the Amendment Date.

 

	
ISIS   PHARMACEUTICALS, INC.
    	
 
    
	
 
    	
 
    	
 
    
	
By:
    	
/s/ B. Lynne Parshall
    	
 
    
	
 
    	
 
    	
 
    
	
Name:
    	
B. Lynne Parshall
    	
 
    
	
 
    	
 
    	
 
    
	
Title:
    	
Chief Operating Officer and Chief Financial   Officer
    	
 
    
	
 
    	
 
    	
 
    
	
Date:
    	
29 October 2012
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
GLAXO   GROUP LIMITED
    	
 
    
	
 
    	
 
    	
 
    
	
By:
    	
/s/ Paul Williamson
    	
 
    
	
 
    	
 
    	
 
    
	
Name:
    	
Paul Williamson
    	
 
    
	
 
    	
 
    	
 
    
	
Title:
    	
Corporate Director
    	
 
    
	
 
    	
 
    	
 
    
	
Date:
    	
29 October 2012
    	
 
    

 

19

 

ATTACHMENT 1

 

TTR Development Plan

 

[***]

 

20

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