FIRST AMENDMENT TO LEASE

Exhibit 10.1

FIRST AMENDMENT TO LEASE

THIS FIRST AMENDMENT TO LEASE (“ First Amendment ”) is made and entered into as of the 23 ^rd day of September, 2008, by and between MULLROCK 3 TORREY PINES, LLC, a Delaware limited liability company (“ Landlord ”) and OREXIGEN THERAPEUTICS, INC., a Delaware corporation (“ Tenant ”).

R E C I T A L S :

A. Landlord and Tenant entered into that certain Office Lease dated as of December 7, 2007 (the “ Lease ”), whereby Landlord leased to Tenant and Tenant leased from Landlord certain office space located in that certain building located and addressed at 3344 North Torrey Pines Court, San Diego, California (the “ Building ”).

B. By this First Amendment, Landlord and Tenant desire to expand the Existing Premises (as defined below) and to otherwise modify the Lease as provided herein.

C. Unless otherwise defined herein, capitalized terms as used herein shall have the same meanings as given thereto in the Lease.

NOW, THEREFORE, in consideration of the foregoing recitals and the mutual covenants contained herein, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties hereto hereby agree as follows:

A G R E E M E N T :

1. The Existing Premises . Landlord and Tenant hereby agree that pursuant to the Lease, Landlord currently leases to Tenant and Tenant currently leases from Landlord approximately 22,229 rentable and 19,818 usable square feet (consisting of 9,628 rentable and 8,584 usable square feet of space on the first (1 ^st ) floor of the Building and 12,601 rentable and 11,234 usable square feet of space on the second (2 ^nd ) floor of the Building) (collectively, the “ Existing Premises ”), as more particularly described in the Lease.

2. Expansion of the Existing Premises; Expansion Commencement Date .

2.1. Expansion Space . That certain space located on the plaza level of the Building containing approximately 9,312 rentable (8,281 usable) square feet in the Building as outlined on the floor plan attached hereto as Exhibit “A” and made a part hereof, may be referred to herein as the “ Expansion Space .”

2.2. Expansion Commencement Date . Effective as of the date (“ Expansion Commencement Date ”) that is the later of (i) April 1, 2009 or (ii) the date of Substantial Completion of the Improvements (as defined in the Work Letter Agreement attached hereto as Exhibit “B”) (or the date Substantial Completion would have occurred but for Tenant Delays (as defined in Exhibit “B”)), Tenant shall lease from Landlord and Landlord shall lease to Tenant the Expansion Space. Accordingly, effective upon the Expansion Commencement Date, the Existing Premises shall be increased to include the Expansion Space. Landlord and Tenant hereby stipulate and agree that such addition of the Expansion Space to the Existing Premises shall, effective as of the Expansion Commencement Date, increase the number of square feet leased by Tenant in the Project to a total of 31,541 rentable (28,099 usable) square feet. Effective as of the Expansion Commencement Date, all references to the “Premises” shall mean and refer to the Existing Premises as expanded by the Expansion Space.

3. Expansion Space Term . The term of the Lease of the Expansion Space shall commence as of the Expansion Commencement Date and shall terminate on the July 31, 2013 lease expiration date (“ Lease Expiration Date ”). The period from the Expansion Commencement Date through the Lease Expiration Date shall be referred to herein as the “ Expansion Space Term .”

4. Monthly Basic Rent for the Expansion Space . Effective as of the Expansion Commencement Date, Tenant shall pay, in accordance with the provisions of this Section 4, and subject to abatement pursuant to Section 5 below, Monthly Basic Rent for the Expansion Space as follows:

5. Monthly Basic Rent Abatement . Notwithstanding anything to the contrary contained in the Lease or in this First Amendment, and provided that Tenant faithfully performs all of the terms and conditions of the Lease, as amended by this First Amendment, Landlord hereby agrees to abate Tenant’s obligation to pay Monthly Basic Rent for the second (2 ^nd ) month of the Expansion Space Term. During such abatement period, Tenant shall still be responsible for the payment of all of its other monetary obligations under the Lease, as amended by this First Amendment.

6. Tenant’s Percentage and Base Year . Notwithstanding anything to the contrary in the Lease, commencing as of the Expansion Commencement Date and continuing during the Expansion Space Term, Tenant’s Percentage for the Premises (including the Existing Premises and the Expansion Space) shall be 68.21% and the Base Year for the Expansion Space shall be the calendar year 2009. The Base Year for the Existing Premises shall remain the calendar year 2008. The total rentable square feet of the Building is 46,238 feet, and the total square feet leased by Tenant in the Project is 31,541 rentable (28,099 usable) square feet.

7. Additional Exterior Sign . Subject to the approval of all applicable governmental and quasi-governmental entities, and subject to any covenants, conditions and restrictions and all applicable governmental and quasi-governmental laws, rules, regulations and codes and the terms and conditions of the Lease, Landlord grants Tenant the exclusive right to install one (1) additional exterior sign on the south face of the Building (with the exact location to be determined by Landlord and approved by Tenant such approval not to be unreasonably withheld or delayed) (the “ Additional Exterior Sign ”). Such Additional Exterior Sign shall be at an initial monthly fee to Tenant of Five Hundred Dollars ($500.00) per month (which amount shall be payable by Tenant to Landlord at the same time and in the same manner as Monthly Basic Rent is payable by Tenant under the Lease) and which monthly fee is subject to increase during the Option Term described in Section 2.2 of the Lease. All of the other terms, conditions and provisions of Section 6.2(b) of the Lease (pertaining to Tenant’s Exterior Signage) shall apply to Tenant’s rights to the Additional Exterior Sign.

8. Brokers . Each party represents and warrants to the other that no broker, agent or finder negotiated or was instrumental in negotiating or consummating this First Amendment other than The Muller Company (“ Landlord’s Broker ”) and The Staubach Company-San Diego, Inc. (“ Tenant’s Broker ”). Each party further agrees to defend, indemnify and hold harmless the other party from and against any claim for commission or finder’s fee by any entity (other than Landlord’s Broker or Tenant’s Broker) who claims or alleges that they were retained or engaged by the first party or at the request of such party in connection with this First Amendment.

9. Parking . Effective as of the Expansion Commencement Date, Tenant shall be entitled to an additional twenty-two (22) unreserved, uncovered parking privileges and three (3) additional reserved parking privileges in the subterranean garage at the Project, all at no additional cost to Tenant. Tenant’s use of such additional parking privileges shall be subject to all of the terms and provisions of Section 6.2 of the Lease. Effective as of the date hereof, Tenant hereby exercises its right to lease the additional three (3) reserved parking privileges provided to Tenant under Section 1.16 of the Summary of the Lease (at the initial parking rate provided therein and subject to increase during the Option Term as provided therein) except that Tenant’s leasing of such additional three (3) reserved parking spaces shall be irrevocable and Tenant shall not have the right to rescind its obligation to lease such additional three (3) reserved parking spaces).

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10. Condition of the Expansion Space . Except as specifically set forth in the Lease (and the Work Letter Agreement attached hereto), after Landlord substantially completes the Tenant Improvements and subject to Section 11.1 of the Lease, Tenant hereby agrees to accept the Expansion Space in its “as-is” condition and Tenant hereby acknowledges that Landlord, except as provided in the Work Letter Agreement attached hereto as Exhibit “B,” shall not be obligated to provide or pay for any improvement work or services related to the improvement of the Expansion Space. Tenant also acknowledges that Landlord has made no representation or warranty regarding the condition of the Expansion Space.

11. Early Entry . Tenant’s early entry rights are set forth in Section 6.1 of Exhibit “B” attached hereto.

12. Existing Letter of Credit; Additional Letter of Credit .

12.1. Existing Letter of Credit . Tenant has previously deposited with Landlord a Letter of Credit in the initial amount of One Million Dollars ($1,000,000.00) (“ Existing Letter of Credit ”). Landlord shall continue to hold the Existing Letter of Credit, subject to any reduction per the terms of the Lease, in accordance with the terms and conditions of Section 5 of the Lease.

12.2. Additional Letter of Credit . Concurrently with Tenant’s execution and delivery of this First Amendment to Landlord, Tenant shall deliver to Landlord, as protection for Landlord to assure the full and faithful performance by Tenant of all of its obligations under the Lease (as modified by this First Amendment) and for all losses and damages Landlord may suffer as a result of any default (beyond the expiration of all applicable notice and cure periods) by Tenant under the Lease (as modified by this First Amendment), an irrevocable and unconditional negotiable letter or letters of credit (collectively, the “ Letter of Credit ”), in substantially the form as the Existing Letter of Credit, running in favor of Landlord issued by Silicon Valley Bank, or such other bank that is reasonably acceptable to Landlord (“ Bank ”), and under the supervision of the Superintendent of Banks of the State of California, in the initial amount, in the aggregate, of Four Hundred Twenty Thousand Dollars ($420,000.00) (“ Stated Amount ”); provided, however, that, except as hereinafter provided, commencing on the first (1 ^st ) anniversary of the Expansion Commencement Date and on each annual anniversary of the Expansion Commencement Date thereafter (each, an “ Adjustment Date ”), the Stated Amount shall, subject to the terms hereof, be reduced, in the aggregate, as follows:

However, if (i) a default (beyond the expiration of all applicable notice and cure periods) by Tenant occurs under the Lease (as modified by this First Amendment), or (ii) circumstances exist that would, with notice or lapse of time, or both, constitute a default by Tenant, and Tenant has failed to cure such default within the cure period permitted by Section 23 of the Lease or such lesser time as may remain before the relevant Adjustment Date as provided above, the Stated Amount shall not thereafter be reduced unless and until such default shall have been fully cured pursuant to the terms of the Lease, at which time the Stated