AMENDMENT NO. 1 TO THE THIRD AMENDED AND RESTATED INVESTORS’ RIGHTS AGREEMENT

EXHIBIT 4.2

AMENDMENT NO. 1 TO THE THIRD AMENDED AND RESTATED

INVESTORS’ RIGHTS AGREEMENT

This AMENDMENT NO. 1 THE THIRD AMENDED AND RESTATED INVESTORS’ RIGHTS AGREEMENT is dated as of December 28, 2007 (this “Amendment”) and is entered into by and among NeurogesX, Inc., a Delaware corporation (the “Company”), the parties defined as “Investors” in the XXX (as defined below) (each a “Prior Investor,” and collectively, the “Prior Investors”), and the parties listed on Exhibit A to the SPA (as defined below) (each a “Purchaser,” and collectively, the “Purchasers”). The Third Amended and Restated Investors’ Rights Agreement dated as of November 14, 2005, as amended, shall be hereinafter referred to as the “XXX.”

RECITALS

WHEREAS, The Purchasers are purchasing shares of Common Stock of the Company (the “Shares”) and warrants to purchase shares of Common Stock of the Company (the “Warrants”) pursuant to a Securities Purchase Agreement, dated as of December 23, 2007, by and among the Company and the Purchasers (the “SPA”);

WHEREAS, the Company and the undersigned Prior Investors (on behalf of all Prior Investors) desire the Purchasers to have certain registration rights with respect to the Shares and the shares of Common Stock of the Company issuable upon exercise of the Warrants (the “Underlying Shares,” along with the Shares, collectively, the “Securities”) pursuant to Sections 1.1 through 1.4 and Sections 1.6 through 1.14 of the XXX, by and among the Company and the Prior Investors, and that the Purchasers be added to the Rights Agreement as parties thereto for the purpose of granting such registration rights;

WHEREAS, Section 4.3 of the XXX allows the amendment or waiver of such XXX with the written consent of the Company and the holders of at least a majority Registrable Securities, as defined in the XXX, outstanding (the “Majority Holders”); and

NOW, THEREFORE, in consideration of the promises contained herein and for other good and valuable consideration, the receipt and sufficiency of which is hereby mutually acknowledged by the parties hereto, the parties hereby covenant and agree as follows:

1. The Securities shall constitute “Registrable Securities,” as such term is defined in Section 1.1(g) of the XXX, for all intents and purposes of the registration rights and related provisions and obligations set forth in Sections 1.1 through 1.4, Sections 1.6 through 1.14 and Section 4 of the XXX.

2. The Purchasers shall be treated for all purposes under Sections 1.1 through 1.4, Sections 1.6 through 1.14, and Section 4 of the XXX as “Holders,” as such term is defined in Section 1.01(d) of the XXX; provided however, that the Purchasers shall not be considered “Initiating Holders” as such term is defined in Section 1.1(e).

3. Notwithstanding the foregoing, if the Registration Statement on Form S-3 required to be filed pursuant to the Registration Rights Agreement, dated as of December 23, 2007, by and among the Company and the Purchasers (the “RRA”), is not declared effective or ceases to be effective, or if Form S-3 is not available to the Company to register the Securities under Rule I.B.1 of Form S-3, the Purchasers shall have the right to request up to two demand registrations for underwritten public offerings pursuant to the terms of Section 1.2 of the XXX as if the Purchasers were “Initiating Holders” under such section (without regard, except as set forth below, to the share and dollar threshold requirements set forth in Sections 1.1(e) and 1.2(a)(A), respectively, of the XXX), provided, however, that the Company shall not be required to carry out any such demand registration unless such registration is requested in writing after June 30, 2008 by Purchasers holding at least 30% of the Securities. The Purchaser’s rights to demand registration pursuant to this Section 3 shall terminate two years after the Initial Closing Date, as defined in the RRA.

4. The Purchasers agree to be bound by the terms and conditions of Sections 1.1 through 1.4, Sections 1.6 through 1.14 and Section 4 of the Rights Agreement and shall succeed to and assume all of the rights and obligations of Holders of Registrable Securities for all intents and purposes of such Sections, provided that, the Purchasers shall not be deemed to possess any rights set forth in Sections 2 or 3 of the Rights Agreement.

5. All notices and other communications under the XXX shall be made to the Purchasers at the addresses specified in Exhibit A to the SPA, and thereafter at such other address, notice of which is given in accordance with Section 4.4 of the XXX.

6. To facilitate the sale and issuance of the Securities and the proposed registration of the Securities pursuant to a Registration Statement on Form S-3 under the RRA, the Prior Investors (on their own behalf and on behalf of all Prior Investors for purposes of the XXX) furthermore hereby waive the following as such apply to such Form S-3 registration of the Securities: (i) any right to prior or other notice of a Form S-3 registration carried out pursuant to the RRA; (ii) the 20 day period, set forth in Section 1.3 of the XXX, in which the Prior Investors may otherwise be able to respond to notice by the Company of a Form S-3 registration carried out pursuant to the RRA; (iii) any and all registration rights under the XXX that would require the Company to register in a Form S-3 registered pursuant to the RRA any shares of Company Common Stock held by the Prior Investors; and (iv) any other conflict that may arise between the XXX and the RRA.

7. The Prior Investors hereby (on their own behalf and on behalf of all Prior Investors for purposes of the XXX) consent to the grant to the Purchasers of the piggyback and demand registration rights set forth herein, and hereby waive any conflicts that may arise between the terms hereof and the terms of the XXX.

8. The XXX as modified herein shall remain in full force and effect as so modified.

[Signature Pages Follow]

IN WITNESS WHEREOF, the parties hereto have executed this Amendment as of the date first written above.

NEUROGESX, INC.
By:		/s/ Xxxxxxx Xxxxxxxxx
Name:		Xxxxxxx Xxxxxxxxx
Title:		Chief Financial Officer

THE PURCHASER’S SIGNATURE TO THE INVESTOR QUESTIONNAIRE DATED OF EVEN DATE HEREWITH SHALL CONSTITUTE THE PURCHASER’S SIGNATURE TO THIS AMENDMENT NO. 1 THE THIRD AMENDED AND RESTATED INVESTORS’ RIGHTS AGREEMENT.

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Alta California Partners II, L.P.
By:		Alta California Management Partners II, LLC
Its:		General Partner
By:		/S/ XXXX XXXXXXX
		Member
Alta Embarcadero Partners II, LLC
By:		/S/ XXXX XXXXXXX
		Under Power of Attorney
Alta California Partners II, L.P. – New Pool
By:		Alta California Management Partners II, LLC – New Pool, its General Partner
By:		/S/ XXXX XXXXXXX
		Managing Director
Alta BioPharma Partners III, L.P.
By:		Alta BioPharma Management III, LLC
By:		/S/ XXXX XXXXXXX
		Director
Alta BioPharma Partners III GmbH & Co. Beteiligungs KG
By:		Alta BioPharma Management III, LLC
By:		/S/ XXXX XXXXXXX
		Director
Alta Embarcadero BioPharma Partners III, LLC
By:
		V.P. of Finance & Admin

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

ARCH Venture Fund V, L.P.
By:		ARCH Venture Partners V, L.P.
Its:		General Partner
		By:		ARCH Venture Partners V, LLC
		Its:		General Partner
By:		/S/ XXXXXXX XXXXX
Its:		Managing Director
ARCH V Entrepreneurs Fund, L.P.
By:		ARCH Venture Partners V, L.P.
Its:		General Partner
		By:		ARCH Venture Partners V, LLC
		Its:		General Partner
By:		/S/ XXXXXXX XXXXX
Its:		Managing Director
Healthcare Focus Fund, L.P.
By:		ARCH Venture Partners V, L.P.
Its:		General Partner
		By:		ARCH Venture Partners V, LLC
		Its:		General Partner
By:		/S/ XXXXXXX XXXXX
Its:		Managing Director

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Montreux Equity Partners II, SBIC, L.P.
By:		Montreux Equity Management II SBIC, LLC, its General Partner
By:		/S/ XXXXXX X. XXXXXX
Name:		Xxxxxx X. Xxxxxx III
Title:		Managing Member
Montreux Equity Partners III, SBIC, L.P.
By:		Montreux Equity Management III SBIC, LLC, its General Partner
By:		/S/ XXXXXX X. XXXXXX
Name:		Xxxxxx X. Xxxxxx III
Title:		Managing Member

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Pacven Xxxxxx Ventures V, L.P.
By:
		Lip-Bu Tan
Title:		Director of Pacven Xxxxxx Management V, Co., Ltd. as General Partner of Pacven Xxxxxx Ventures V, L.P.
Pacven Xxxxxx Ventures Parallel V-A, C.V.
By:
		Lip-Bu Tan
Title:		Director of Pacven Xxxxxx Management V, Co., Ltd. as General Partner of Pacven Xxxxxx Ventures Parallel V-A C.V.
Pacven Xxxxxx Ventures Parallel V-B, C.V.
By:
		Lip-Bu Tan
Title:		Director of Pacven Xxxxxx Management V, Co., Ltd. as General Partner of Pacven Xxxxxx Ventures Parallel V-B C.V.
Pacven Xxxxxx Ventures V Associates Fund, L.P.
By:
Title:		Director of Pacven Xxxxxx Management V, Co., Ltd. as General Partner of Pacven Xxxxxx Ventures V Associates Fund, L.P.

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

Pacven Xxxxxx Ventures V-OP Associates Fund, L.P.
By:
		Lip-Bu Tan
Title:		Director of Pacven Xxxxxx Management V, Co., Ltd. as General Partner of Pacven Xxxxxx Ventures V-QP Associates Fund, L.P.
International Venture Capital Investment III Corporation
By:
		Lip-Bu Tan
Title:		President
International Venture Capital Investment Corporation
By:
		Lip-Bu Tan
Title:		President
Asian Venture Capital Investment Corporation
By:
		Lip-Bu Tan
Title:		President
Seed Ventures III Pte. Ltd.
By:
		Lip-Bu Tan, Director

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Dow Employees’ Pension Plan
By:		Diamond Capital Management Inc.
		Its Agent
By:
Name:		Xxxxxxx X. Van Heel
Title:		Sr. Investment Manager
Union Carbide Employees’ Pension Plan
By:		Diamond Capital Management Inc.
		Its Agent
By:
Name:		Xxxxxxx X. Van Heel
Title:		Sr. Investment Manager

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

The Global Life Sciences Ventures Funds II GmbH & Co. KG
Represented by its General Partners
The Global Life Science Ventures GmbH
By:
Title:
The Global Life Sciences Ventures Fund II Limited Partnership
Represented by its General Partner
Global Life Science Ventures (GP) Limited
By:		/S/ XX XXXXXX
Title:		Director

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Xxxx-Xxxxxxx Xxxxxxxx

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

MC Life Science Ventures, Inc.
By:
Name:		Xxxxxxxxx Xxxxxxxxxx
Title:		President

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

XxxXxx International Ltd.

By:

Name:

Title:

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Saudi Venture Development Company

By:

Name:

Title:

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]

PRIOR INVESTORS:

Xxxxxxxx Children’s Irrevocable Trust fbo

Alexis Xxxxxx Xxxxxxxx

By:

Title:

Xxxxxxxx Children’s Irrevocable Trust fbo

Xxxxxxxx Xxxxxx Xxxxxxxx

By:

Title:

Xxxxxxxx Children’s Irrevocable Trust fbo

Xxxxxxx Xxxxxxxx Xxxxxx

By:

Title:

[Signature Page to Amendment No. 1 to the Third Amended and Restated Investors’ Rights Agreement]