<PAGE>

                                                                  EXHIBIT 10.284

                               [Ligand Letterhead]

March 11, 2005

Andres Negro-Vilar, M.D., Ph.D.
Executive Vice President, Research and
Development, & Chief Scientific Officer
LIGAND PHARMACEUTICALS INCORPORATED
10275 Science Center Drive
San Diego, CA 92121

Dear Andres:

            The purpose of this letter agreement is to document the terms of the
severance package to which you will be entitled should your employment with
Ligand Pharmaceuticals Incorporated (the "Company") terminate under certain
specified circumstances.

            Part One of this letter agreement sets forth certain definitional
provisions to be in effect for purposes of determining your benefit
entitlements. Part Two specifies the terms and conditions upon which you may
become entitled to receive severance benefits. Severance benefits accrue under
this letter agreement in the event your employment with the Company were to be
terminated involuntarily in connection with certain changes in control of the
Company. Part Three concludes this letter agreement with a series of general
terms and conditions applicable to your severance benefits.

                             PART ONE -- DEFINITIONS

            Definitions. For purposes of this letter agreement, including in
particular the application of the special benefit limitations of Part Three, the
following definitions will be in effect:

   1. Average Compensation means your average W-2 wages from the Company for the
      five (5) calendar years completed immediately prior to the calendar year
      in which the Change in Control is effected. Any W-2 wages for a partial
      year of employment will be annualized, in accordance with the frequency
      with which such wages are paid during such partial year, before inclusion
      within your Average Compensation.

   2. Board means the Company's Board of Directors.

<PAGE>

   3. Change in Control means any of the following events:

            (i) a merger or consolidation in which the Company is not the
      surviving entity, except for a transaction the principal purpose of which
      is to change the state in which the Company is incorporated,

            (ii) the sale, transfer or other disposition of all or substantially
      all of the assets of the Company other than in the ordinary course of
      business,

            (iii) any reverse merger in which the Company ceases to exist as an
      independent corporation and becomes the subsidiary of another corporation,
      except where there is an insubstantial change in the de facto voting
      control of the Company (e.g. the creation of a holding company),

            (iv) any Hostile Take-Over,

            (v) the acquisition by any person (or related group of persons),
      whether by tender or exchange offer made directly to the Company's
      stockholders, private purchases from one or more of the Company's
      stockholders, open market purchases or any other transaction, of
      beneficial ownership of securities possessing more than thirty percent
      (30%) of the total combined voting power of the Company's outstanding
      securities,

            (vi) the acquisition by any person (or related group of persons),
      whether by tender or exchange offer made directly to the Company's
      stockholders, private purchases from one or more of the Company's
      stockholders, open market purchases or any other transaction, of
      additional securities of the Company which increase the total holdings of
      such person (or group) to a level of securities possessing more than fifty
      percent (50%) of the total combined voting power of the Company's
      outstanding securities, or

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 3

             (vii) the acquisition by any person (or related group of persons),
       whether by tender or exchange offer made directly to the Company's
       stockholders, private purchases from one or more of the Company's
       stockholders, open market purchases or any other transaction, of
       securities of the Company possessing sufficient voting power in the
       aggregate to elect an absolute majority of the members of the Board
       (rounded up to the nearest whole number).

   4.  COBRA means the continuation-of-coverage provisions of the Consolidated
       Omnibus Budget Reconciliation Act of 1985, as amended.

   5.  Code means the Internal Revenue Code of 1986, as amended.

   6.  Common Stock means the Company's common stock, par value $0.001 per
       share.

   7.  Equity Incentive Plans means any of the following equity incentive plans
       of the Company: 1992 Stock Option/Stock Issuance Plan, the 2002 Stock
       Incentive Plan, and the Restricted Stock Purchase Plan, together with any
       amendments or successors to such plans.

   8.  Equity Parachute Payment means, with respect to any Option (whether
       Acquisition-Accelerated or Severance-Accelerated) or unvested Stock
       Issuance, the portion deemed to be a parachute payment under Code Section
       280G and the Treasury Regulations issued thereunder. Such Equity
       Parachute Payment shall be calculated in accordance with the valuation
       provisions established under Code Section 280G and the applicable
       Treasury Regulations and will include an appropriate dollar adjustment to
       reflect the lapse of your obligation to remain in the Company's employ as
       a condition to your vesting in the accelerated portion of such Option or
       Stock Issuance.

   9.  ERISA means the Employee Retirement Income Security Act of 1974, as
       amended.

   10. Health Care Coverage means the health care benefits provided by the
       Company to you and your eligible dependents for which you are eligible to
       continue coverage under the provisions of COBRA.

   11. Hostile Take-Over means either of the following events:

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 4

            (i) the acquisition by any person (or related group of persons)
      whether by tender or exchange offer made directly to the Company's
      stockholders, private purchases from one or more of the Company's
      stockholders, open market purchases or any other transaction, of
      beneficial ownership of securities possessing more than thirty percent
      (30%) of the total combined voting power of the Company's outstanding
      securities pursuant to a tender offer made directly to the Company's
      stockholders which the Board does not recommend such stockholders to
      accept, or

            (ii) a change in the composition of the Board over a period of
      thirty-six (36) consecutive months or less such that a majority of the
      Board members (rounded up to the next whole number) ceases, by reason of
      one or more contested elections for Board membership, to be comprised of
      individuals who either (a) have been Board members continuously since the
      beginning of such period or (b) have been elected or nominated for
      election as Board members during such period by at least a majority of the
      Board members described in clause (a) who were still in office at the time
      such election or nomination was approved by the Board.

   12. Involuntary Termination means the termination of your employment with the
       Company:

            (i) upon your involuntary discharge or dismissal, or

            (ii) upon your resignation in connection with any of the following
      changes to the terms and conditions of your employment: (A) a change in
      your position with the Company which materially reduces your level of
      responsibility, (B) a greater than ten percent (10%) reduction in your
      level of compensation (including base salary, fringe benefits and
      participation in non-discretionary bonus programs under which awards are
      payable pursuant to objective financial or performance standards, but
      excluding equity compensation) or (C) a relocation of your principal place
      of employment by more than fifty (50) miles.

            The following guidelines shall determine whether one or more
      reductions in compensation should be taken into account for purposes of
      clause (ii)(B):

            (a) Any reduction in compensation which occurs in connection

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 5

       with an across-the-board reduction in the level of compensation payable
       to the Company's executive officers or senior management shall not
       constitute grounds for a clause (ii)(B) resignation, unless implemented
       within eighteen (18) months after a Change in Control.

            (b) In the event of a Hostile Take-Over, the greater than ten
       percent (10%) standard of clause (ii)(B) shall be reduced to zero percent
       (0%) so that any reduction in the level of your compensation shall
       constitute grounds for a clause (ii)(B) resignation.

            In no event shall an Involuntary Termination be deemed to occur
       should your employment terminate by reason of death or permanent
       disability.

   13. Option means any option granted to you under any of the Equity Incentive
       Plans which is outstanding at the time of your Involuntary Termination or
       any earlier Change in Control. Your outstanding options are to be divided
       into two separate categories as follows:

            (i) Acquisition-Accelerated Options: any outstanding Option (or
       installment thereof) which accelerates upon a Change in Control in
       accordance with the automatic acceleration provisions of the Equity
       Incentive Plans.

            (ii) Severance-Accelerated Options: any outstanding Option (or
       installment thereof) which is not an Acquisition-Accelerated Option but
       which accelerates upon your Involuntary Termination, whether or not in
       connection with a Change in Control, as part of your severance benefits
       under this letter agreement.

   14. Other Parachute Payments mean any payments in the nature of compensation
       to which you may become entitled under this letter agreement (other than
       the Equity Parachute Payment) or any other arrangement with the Company,
       to the extent such payments qualify as parachute payments within the
       meaning of Code Section 280G(b)(2) and the Treasury Regulations issued
       thereunder or would so qualify if the aggregate present value of such
       payments exceeded the amount specified in Code Section 280G(b)(2)(ii).

   15. Stock Issuance means the issuance of unvested shares of Common Stock
       under the Company's Restricted Stock Plan or any other Equity Incentive
       Plan.

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 6

   16. Termination for Cause means an Involuntary Termination or resignation of
       your employment with the Company by reason of your conviction of any
       felony or other criminal act, your commission of any act of fraud or
       embezzlement, your unauthorized use or disclosure of confidential or
       proprietary information or trade secrets of the Company or its
       subsidiaries, or any other intentional misconduct on your part which
       adversely affects the business or affairs of the Company in a material
       manner.

                  PART TWO -- INVOLUNTARY TERMINATION BENEFITS

            You will be entitled to receive the severance benefits specified
below should there occur an Involuntary Termination of your employment during
the term of this letter agreement effected in connection with a Change in
Control, other than a Termination for Cause. However, in the absence of a
Hostile Take-Over, these benefits will continue to be paid you only for so long
as you remain available for any consulting services required of you under Part
Two, Paragraph 4 and abide by the restrictive covenants set forth in Part Two,
Paragraph 5.

   1.  Severance Payments. You will receive severance payments from the Company
       for a period of twelve (12) months following your Involuntary Termination
       in an aggregate amount equal to the sum of (A) one (1) times the annual
       rate of base salary in effect for you at the time of your Involuntary
       Termination or at the time of the relevant Change in Control, whichever
       is higher plus (B) one (1) times the average of the bonuses (excluding
       any signing bonus) paid to you for services rendered in the two (2)
       fiscal years immediately preceding the fiscal year of your Involuntary
       Termination (annualized if paid for a partial fiscal year). If a bonus is
       paid to you for only one of those years, then the bonus amount under
       Clause (B) will be equal to one (1) times such bonus amount. The
       aggregate severance payments shall be paid to you in equal installments
       over the twelve-month period in accordance with the Company's normal
       payroll practices and subject to all applicable withholding taxes. The
       severance payments will immediately terminate if and only if (i) you
       should cease to remain available for the consulting services required of
       you under Section 4, or (ii) you fail to abide by the restrictive
       covenants set forth in Section 5 . However, in the event your Involuntary
       Termination occurs in connection with a Hostile Take-Over, your severance
       payments will be paid to you in the form of a single lump sum amount
       within thirty (30) days after such Involuntary Termination, and the
       provisions of

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 7

      Sections 4 and 5 of this Part Two will not apply.

   2. Health Care Coverage. The Company will, at its expense, make any COBRA
      payments for you and your eligible dependents in order to continue your
      Health Care Coverage until the earlier of (i) twelve (12) months after the
      effective date of your Involuntary Termination (other than a Termination
      for Cause) or (ii) the first date that you are covered under another
      employer's (or, in the event of rehire, the Company's) health benefit
      program which provides substantially the same level of benefits without
      exclusion for pre-existing medical conditions. Such payments will be in
      lieu of any other continued health care coverage to which you or your
      dependents would otherwise be entitled pursuant to the requirements of
      Code Section 4980B by reason of your termination of employment.

   3. Option Acceleration and Lapse of Restrictions. Each of your outstanding
      Options under the Equity Incentive Plans will (to the extent not then
      otherwise exercisable) automatically accelerate so that each such Option
      will become immediately exercisable for the total number of shares of
      Common Stock at the time subject to that Option. Each such accelerated
      Option, together with all of your other vested Options, will remain
      exercisable for a period of twelve (12) months following your Involuntary
      Termination until the end of the specified ten (10)-year option term. Such
      Option(s) may be exercised for any or all of the option shares in
      accordance with the exercise provisions of the option agreement evidencing
      the grant. In addition, all restrictions applicable to the Stock Issuances
      you hold (to the extent those restrictions have not previously lapsed in
      accordance with the terms of the issuance agreements) will automatically
      lapse upon your Involuntary Termination (except a Termination for Cause).

   4. Consulting Services. Unless your Involuntary Termination occurs in
      connection with a Hostile Take-Over, you will make yourself available to
      perform consulting services reasonably requested of you during the twelve
      (12)-month period following your Involuntary Termination. You will be
      compensated at an hourly rate to be agreed upon by you and the Company at
      the time such consulting services are to be rendered, and you will be
      reimbursed for all reasonable out-of-pocket expenses incurred in rendering
      such services upon your submission of appropriate documentation for those
      expenses.

   5. Restrictive Covenants. For the one hundred twenty (120)-day period
      following your Involuntary Termination:

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 8

            (i) You will not directly or indirectly, whether for your own
      account or as an employee, director, consultant or advisor, provide
      services to any business enterprise which is at the time in competition
      with any of the Company's then existing or formally planned product lines
      and which is located geographically in an area where the Company maintains
      substantial business activities, unless you obtain the prior written
      consent of the Board of Directors.

            (ii) You will not directly or indirectly encourage or solicit any
      individual to leave the Company's employ for any reason or interfere in
      any other manner with the employment relationships at the time existing
      between the Company and its current or prospective employees.

            (iii) You will not induce or attempt to induce any customer,
      supplier, distributor, licensee or other business relation of the Company
      to cease doing business with the Company or in any way interfere with the
      existing business relationship between any such customer, supplier,
      distributor, licensee or other business relation and the Company.

      You acknowledge that monetary damages may not be sufficient to compensate
      the Company for any economic loss which may be incurred by reason of your
      breach of the foregoing restrictive covenants. Accordingly, in the event
      of any such breach, the Company shall, in addition to the cessation of the
      severance benefits provided you under this letter agreement and any
      remedies available to the Company at law, be entitled to obtain equitable
      relief in the form of an injunction precluding you from continuing to
      engage in such breach.

      None of the foregoing restrictive covenants in this section 5 shall be
      applicable in the event your Involuntary Termination occurs in connection
      with a Hostile Take-Over.

   6. Benefit Reduction.

            (i) Benefit Reduction. If the Change in Control does not constitute
      a Hostile Take-Over, first the dollar amount of your severance payment
      under Paragraph 1 will be reduced to the extent necessary to assure that
      the present value of those benefits will not, when added to the present
      value of your Equity Parachute Payment and your Other Parachute Payments,
      exceed 2.99 times your Average Compensation. In the event of a Hostile
      Take-Over, no reduction will be made to your severance payment (or any
      other benefit to which you become entitled hereunder), unless necessary to
      provide you with the

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 9

      maximum after-tax benefit available, after taking into account any
      parachute excise tax which might otherwise be payable by you under Code
      Section 4999 and any analogous State income tax provision.

            (ii) Resolution of Disputes. In the event there is any disagreement
      between you and the Company as to whether one or more benefits to which
      you become entitled (whether under this letter agreement or otherwise) in
      connection with a Change in Control constitute Equity Parachute Payments
      or Other Parachute Payments, such dispute is to be resolved as follows:

                  A. The matter shall be submitted for resolution to independent
      counsel mutually acceptable to you and the Company ("Independent
      Counsel"). The resolution reached by Independent Counsel shall be final
      and controlling. However, should the Independent Counsel determine that
      the status of the benefits in dispute can be resolved by obtaining a
      private letter ruling from the Internal Revenue Service, a formal and
      proper request for such ruling shall be prepared and submitted by
      Independent Counsel, and the determination made by the Internal Revenue
      Service in the issued ruling shall be controlling. All expenses incurred
      in connection with the retention of Independent Counsel and (if
      applicable) the preparation and submission of the ruling request shall be
      paid by the Company.

                  B. The present value of each Equity Parachute Payment and each
      of the Other Parachute Payments (including your severance payment and
      Health Care Coverage) shall be determined in accordance with the
      provisions of Code Section 280G(d)(4) and the Treasury Regulations issued
      thereunder.

      The full amount of your severance benefit under Paragraph 1 shall not be
      paid to you until any amounts in dispute under this Paragraph 6(ii) have
      been resolved in accordance herewith. However, any portion of such
      severance payment which would not otherwise exceed the benefit limitation
      of Paragraph 6(i) even if all amounts in dispute under this Paragraph
      6(ii) were to be resolved against you will be paid to you in accordance
      with the applicable provisions of this letter agreement.

            (iii) Overriding Limitation. You will in all events be entitled to
      receive the full amount of your severance payment under Paragraph 1, to
      the extent those benefits, when added to the present value of your Equity
      Parachute Payment and your Other Parachute Payments (excluding such
      severance payment), will nevertheless qualify as reasonable compensation
      within the

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 10

      standards established under Code Section 280G(b)(4).

            (iv) Interpretation. The provisions of this Section 6 shall in all
      events be interpreted in such manner as will avoid the imposition of
      excise taxes under Code Section 4999, and the disallowance of deductions
      under Code Section 280G(a), with respect to your severance benefits under
      this letter agreement.

                     PART THREE -- MISCELLANEOUS PROVISIONS

   1. Termination for Cause. Should your termination constitute a Termination
      for Cause, then the Company shall only be required to pay you (i) any
      unpaid compensation earned for services previously rendered through the
      date of such termination and (ii) any accrued but unpaid vacation benefits
      or sick days, (iii) any reimbursements then owed to you by the Company and
      no benefits will be payable to you under this letter agreement.

   2. Term of Agreement. The provisions of this letter agreement will continue
      in effect for a period of five (5) years from the date hereof.

   3. General Creditor Status. The benefits to which you may become entitled
      under this letter agreement (except those attributable to your Options or
      Stock Issuances) will be paid, when due, from the general assets of the
      Company. Your right (or the right of the executors or administrators of
      your estate) to receive any such payments will at all times be that of a
      general creditor of the Company and will have no priority over the claims
      of other general creditors of the Company.

   4. Death. Should you die before receipt of all benefits to which you become
      entitled under this letter agreement, then the payment of such benefits
      will be made, on the due date or dates hereunder had you survived, to the
      executors or administrators of your estate. Should you die before you
      exercise your Severance-Accelerated Options (if any) or any other of your
      outstanding vested Options, then each such Option may be exercised, during
      the applicable exercise period in effect hereunder for those options at
      the time of your death, by the executors or administrators of your estate
      or by person to whom the Option is transferred pursuant to your will or in
      accordance with the laws of inheritance.

   5. Miscellaneous. The provisions of this letter agreement will be construed
      and interpreted under ERISA. To the extent ERISA is inapplicable, then the
      laws of the State of California shall control, without regard to that
      state's choice of law

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 11

      provisions. This letter agreement incorporates the entire agreement
      between you and the Company relating to the subject of severance benefits
      and supersedes all prior agreements and understandings with respect to
      such subject matter. This letter agreement may only be amended by written
      instrument signed by you and another duly-authorized officer of the
      Company. If any provision of this letter agreement as applied to any party
      or to any circumstance should be adjudged by an arbitrator or court of
      competent jurisdiction to be void or unenforceable for any reason, the
      invalidity of that provision shall in no way affect (to the maximum extent
      permissible by law) the application of such provision under circumstances
      different from those so adjudicated, the application of any other
      provision of this letter agreement, or the enforceability or invalidity of
      this letter agreement as a whole. Should any provision of this letter
      agreement become or be determined to be invalid, illegal or unenforceable
      in any jurisdiction by reason of the scope, extent or duration of its
      coverage, then such provision shall be deemed amended to the extent
      necessary to conform to applicable law so as to be valid and enforceable
      or, if such provision cannot be so amended without materially altering the
      intention of the parties, then such provision shall be stricken and the
      remainder of this letter agreement shall continue in full force and
      effect.

   6. Remedies. All rights and remedies provided pursuant to this letter
      agreement or by law will be cumulative, and no such right or remedy will
      be exclusive of any other. A party may pursue any one or more rights or
      remedies hereunder or may seek damages or specific performance in the
      event of another party's breach hereunder or may pursue any other remedy
      by law or equity, whether or not stated in this letter agreement.

   7. Arbitration. Any controversy which may arise between you and the Company
      with respect to the construction, interpretation or application of any of
      the terms, provisions or conditions of this letter agreement or any
      monetary claim arising from or relating to this letter agreement will be
      submitted to and exclusively decided by final and binding arbitration in
      San Diego, California in accordance with the rules of the American
      Arbitration Association then in effect.

   8. No Employment or Service Contract. Nothing in this letter agreement shall
      confer upon you any right to continue in the employment of the Company for
      any period of specific duration or interfere with or otherwise restrict in
      any way the rights of the Company or you, which rights are hereby
      expressly reserved by each, to terminate your employment at any time for
      any reason whatsoever, with or without cause.

<PAGE>

Andres Negro-Vilar, M.D., Ph.D.
March 11, 2005
Page 12

   9. Proprietary Information. You hereby acknowledge that the Company may, from
      time to time during your employment with the Company, disclose to you
      confidential information pertaining to the Company's business and affairs.
      All information and data, whether or not in writing, of a private or
      confidential nature concerning the business or financial affairs of the
      Company is and will remain subject to a separate Proprietary Information
      and Inventions Agreement (or the like) between you and the Company.

            Please indicate your acceptance of the foregoing provisions of this
severance agreement by signing the enclosed copy of this letter agreement and
returning it to the Company.

Very truly yours,

LIGAND PHARMACEUTICALS INCORPORATED

/s/ David E. Robinson

David E. Robinson
Chairman, President and CEO


ACCEPTED BY AND AGREED TO

Signature: /s/ Andres Negro-Vilar

Dated: 3/11/05