Exhibit 10.1

CONFIDENTIAL TREATMENT

Dyax Corp. has requested that portions of this document be accorded confidential
treatment pursuant to Rule 24b-2 promulgated under the Securities Exchange Act
of 1934, as amended.

CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012
 
FOURTH AMENDMENT
TO
JOINT DEVELOPMENT AND LICENSE AGREEMENT

This FOURTH AMENDMENT (the "Fourth Amendment"), dated as of May 29, 2012 (the
"Fourth Amendment Date"), is entered into by and between Dyax Corp. ("Dyax"),
and Sigma Tau Rare Diseases S.A. as successor-in-interest to Defiante
Farmacêutica S.A. ("STRD").  This Fourth Amendment further amends that certain
Joint Development and License Agreement (the "Original Agreement"), dated
effective as of June 18, 2010 (the "Effective Date"), as amended by the First
Amendment to Joint Development and License Agreement (the "First Amendment”),
dated December 21, 2010 (the "First Amendment Date"), the Second Amendment to
Joint Development and License Agreement (the "Second Amendment"), dated May 21,
2011 (the "Second Amendment Date") and the Third Amendment to Joint Development
and License Agreement (the "Third Amendment"), dated December 26, 2011 (the
"Third Amendment Date").  The Original Agreement, as amended by the First
Amendment, the Second Amendment and the Third Amendment, is referred to herein
as the "Amended Agreement."   All capitalized terms not otherwise defined in
this Fourth Amendment shall be as defined in the Amended Agreement.

WHEREAS, under the terms of the Amended Agreement, Dyax has granted STRD certain
rights to Develop, Manufacture and Commercialize products incorporating DX-88
for the treatment of angioedemas and certain other indications; and

WHEREAS, the parties wish to amend certain terms and conditions applicable to
STRD's rights and obligations under the Amended Agreement.

NOW, THEREFORE, in consideration of the promises and agreements set forth
herein, and for other good and valuable consideration, the receipt and
sufficiency of which are hereby acknowledged, Dyax and STRD hereby agree as
follows:

1.
All references to Defiante Farmacêutica S.A. (Defiante) contained in the Amended
Agreement shall be deemed to refer to Sigma Tau Rare Diseases S.A. (STRD).

 
 

2.
Exhibit A to the Amended Agreement is hereby deleted in its entirety and
replaced by Exhibit A attached to this Fourth Amendment.   For the avoidance of
doubt, the countries of the Middle East and North Africa, as well as Brazil and
Argentina, have been removed from the STRD Territory and all rights to Develop
and Commercialize Product in such countries has been returned to Dyax.   STRD
shall, within [*****] after the Fourth Amendment Date, transfer to Dyax all
records and materials available to STRD and relating to STRD's Product-related
activities in such countries, including regulatory correspondence and filings,
and copies of any third party agreements, if any (it being understood that Dyax
will have no obligations under any such agreements).

3.
Section 4.2 (a) of the Amended Agreement is hereby deleted in its entirety and
replaced by the following, in lieu thereof:

 
4.2
HAE Indication.

 
 
(a)
HAE Development Plan. As soon as possible after the Fourth Amendment Date, STRD
and Dyax shall jointly complete, and the JSC shall approve by [*****], a formal
document that will detail STRD's [*****] Efforts to Commercialize Product in the
Field in the STRD Territory (the "HAE Development Plan") in accordance with its
obligations under Section 5.1 and, as to Europe, in accordance with the
provisions of Section 6.7 hereof. The HAE Development Plan shall include all
activities that are necessary to obtain Regulatory Approval of the Product in
the Field in the Additional STRD Territory; strategies and timelines for
completing such activities, together with the annual budget for expenses related
thereto.  For the sake of clarity, the HAE Development Plan shall require STRD
to show meaningful progress towards the Commercialization of Product in the
Second Additional STRD Territory by [*****]. The HAE Development Plan shall also
allocate responsibility between the Parties for such activities, subject to
Section 4.2(c), (d) and (e) below and each Party's financial obligations under
Section 7.3.

 
Confidential materials omitted and filed separately with the Securities and
Exchange Commission. 
Asterisks denote such omission.
 
 
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CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012
 
The JSC shall review and monitor the activities conducted by the Parties under
the HAE Development Plan, which shall be updated and modified from time to time
to include any additional studies required by any Regulatory Authority in the
Additional STRD Territory, up until filing of an application for Regulatory
Approval with such Regulatory Authority, and any Post-Filing Activities required
to obtain Regulatory Approval for the treatment of HAE in each country of the
Additional STRD Territory, in accordance with the following process:
 
(i)            
each Party shall review the HAE Development Plan not less frequently than
quarterly and shall develop detailed and specific updates to the HAE Development
Plan, until the completion of the activities covered thereunder;

 
(ii)           
each Party shall submit all such updates to the JSC for review and approval at
each meeting of the JSC; and

 
(iii)          
the JSC shall review proposed updates to the HAE Development Plan at the next
scheduled meeting of the JSC, or earlier if the JSC so agrees, and may approve
such proposed updates in its discretion and, upon such approval by the JSC, the
HAE Development Plan shall be amended accordingly.

 
4.
Section 5.1(b) of the Amended Agreement is hereby deleted in its entirety and
replaced by the following, in lieu thereof:

 
(b)
STRD shall use [*****] Efforts to obtain Regulatory Approval and Commercialize
Product in the Additional STRD Territory for the HAE Indication and any
Additional Indications that are Jointly Developed by the Parties in the
Field.  The parties acknowledge and agree that, among other things, this Section
5.1(b) shall require that STRD shall file for Regulatory Approval of the Product
in the Additional STRD Territory in accordance with the timelines set forth in
the HAE Development Plan to be agreed upon by [*****] (as per Section 4.2
above). Notwithstanding the foregoing, if STRD fails to complete any such
activities in accordance with the applicable timeline set forth in the HAE
Development Plan as a result of Dyax's failure or delay in meeting any
obligation to STRD under this Agreement, then the timeline shall be extended to
reasonably adjust for such failure or delay.

5.
Article VI of the Amended Agreement is hereby amended to insert the following
Section 6.7 at the end of such Article:

 
6.7
Supply of Drug for Named Patient Program in Europe.  Dyax and STRD agree that
STRD may initiate a Named Patient Program in Europe only.  For the purposes of
this Section 6.7, a "Named Patient Program" or "NPP" shall mean a program to
supply Product in accordance with Article 5 of Directive 2001/83/EC applicable
to products which do not have a marketing authorisation for the specific
therapeutic indication for which it is prescribed in the country of destination
and are supplied to meet the special needs of a specific patient under the order
of a medical practitioner or other person lawfully permitted to prescribe such
products to such patient in accordance with applicable laws and regulations in
the relevant country. Solely for Product ordered and used by STRD in connection
with the Named Patient Program in Europe, the following terms and conditions
shall apply:

 
Confidential materials omitted and filed separately with the Securities and
Exchange Commission. 
Asterisks denote such omission.
 
 
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CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012
 
(a)           
Licensed Indications. Product supplied by STRD for use in the Named Patient
Program in Europe may be used in any indication for which it has been prescribed
within the angioedema field (including without limitation hereditary angioedema,
acquired angioedema, drug-induced angioedema and/or idiopathic angioedema).

(b)           
Orders for NPP Product; Delivery.  STRD may order NPP Product at any time and in
any quantities; provided that all such NPP Product shall be delivered by Dyax
Free Carrier / FCA (Incoterms 2010) from Dyax’s manufacturing or storage
facilities.  Alternatively, STRD can request that NPP Product be delivered by
Dyax CIP (ICC Incoterms 2010) to a predetermined facility designated by STRD,
provided that if such a request is made, STRD shall reimburse Dyax for all
shipping-related costs (including insurance).  All NPP Product shall be
delivered within [*****] following the receipt of the relevant purchase order by
Dyax. At the time of delivery, all NPP Product shall have at least [*****] of
shelf life remaining.

(c)           
Manufacturing Specifications and Labeling.  All NPP Product shall be
manufactured, packaged and labeled according to the specifications submitted to
and approved by Regulatory Authorities in the United States of America for the
Product commercialized by Dyax in the United States of America under Dyax’s
Regulatory Approval.

(d)           
Purchase Price.  With respect to any amount of NPP Product delivered by Dyax to
STRD, STRD shall pay to Dyax an amount equal to [*****] of the Manufacturing
Cost for such NPP Product. For the purpose of this Section 6.7 only,
Manufacturing Cost shall be adjusted to include the [*****] under the [*****]
Agreement as a result of applicable NPP Product sales, provided that the total
amount to be paid by STRD for the NPP Product shall in no case be higher than
[*****] per pack of 3 vials (such cap to be adjusted accordingly in case a
different formulation be available). The purchase price shall be due within
[*****] after receipt of an invoice issued by Dyax upon delivery.  No other
payment shall be due from STRD to Dyax in connection with the purchase of NPP
Product, and no milestone payment or Contribution Payment shall be due under
Sections 7.2, 7.4 or 7.5 with respect to sales of NPP Product in Europe.

(e)           
Program Responsibility.  Subject to Article XI of this Agreement, STRD shall be
fully responsible for the conduct of the Named Patient Program in Europe in
accordance with all applicable laws and regulations and terms and conditions of
this Agreement.  Dyax shall provide STRD with all reasonable support required by
the terms of this Agreement in connection with the conduct of the Named Patient
Program in Europe (whether conducted by STRD or its designee).

(f)            
Program Termination. Upon [*****] prior written notice to STRD, Dyax may
terminate the Named Patient Program in Europe if the Product receives Regulatory
Approval in any indication by EMA.

6.
Section 7.2(c) of the Amended Agreement is hereby deleted in its entirety and
replaced by the following, in lieu thereof:

 
(c)
Milestones for the Additional STRD Territory. Within [*****] following the
occurrence of each of the following events by STRD, its Affiliates or
sublicensees with respect to a Product and upon receipt of the relevant invoice,
STRD shall make the following one-time milestone payments to Dyax:

 
Confidential materials omitted and filed separately with the Securities and
Exchange Commission. 
Asterisks denote such omission.
 
 
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CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012
 
  Milestone Event
 
Payment
 (1)
Upon first filing for Regulatory Approval in Australia or New Zealand.
[*****]
 
 (2)
Upon first Regulatory Approval in Australia or New Zealand
[*****]
 
 (3) 
Upon First Commercial Sale in Australia or New Zealand
 
This  milestone shall only be due if STRD is able to secure a price
reimbursement approval for the Product in excess of [*****] per treatment in
Australia or New Zealand
 
[*****]

For the avoidance of doubt, each of the foregoing milestone payments is a
separate payment and shall be paid only once by STRD.  Consequently, the maximum
amount that STRD is obligated to pay to Dyax under this Section 7.2 (c) is
[*****].

7.
Article VII of the Amended Agreement is hereby amended to insert the following
Sections 7.14 at the end of such Article:

 
 
7.14
Contribution Payments by Dyax.

(a)           
Within [*****] following the completion of each calendar quarter during the Term
of this Agreement, Dyax shall pay to STRD a quarterly contribution payment equal
to twelve and one-half percent (12.5%) of any amounts received by Dyax during
the prior quarter as a result of sales of Product in the following
countries:  Morocco, Algeria, Tunisia, Egypt, Libya, Eritrea, Mauritania,
Somalia , Ethiopia, Jordan, Syria, Lebanon, Saudi Arabia, Oman, Bahrain, United
Arab Emirates and the Islamic Republic of Iran.

(b)           
If STRD has not entered into a Distribution Agreement covering the
commercialization of the Product in Turkey on or before [*****], then from and
after such date: (i) STRD's rights under Section 3.1 with respect to the Product
in Turkey will revert back to Dyax; and (ii) Dyax shall pay to STRD  a monthly
contribution payment equal to twelve and one-half percent (12.5%) of any amounts
received by Dyax as a result of sales of Product in Turkey. Such payment shall
be made to STRD within [*****] following the completion of each calendar quarter
during the Term of this Agreement. For the purposes of this provision, the term
"Distribution Agreement" shall mean a binding agreement with a reputable
business entity engaged in the distribution of pharmaceutical products in the
applicable region which has been executed in compliance with Section 3.1(d) of
the Amended Agreement.

8.
Except as expressly provided otherwise in this Fourth Amendment, all provisions
of the Amended Agreement remain in full force and effect without modification
and all such terms are hereby ratified and confirmed.

9.
From and after the Fourth Amendment Date, the term "Agreement" as used in the
Original Agreement shall mean the Original Agreement, as amended by the First
Amendment, the Second Amendment, the Third Amendment and this Fourth Amendment.

10.
This Fourth Amendment may be executed in one or more counterparts, each of which
shall be deemed an original and all of which shall constitute one and the same
instrument.

 
Confidential materials omitted and filed separately with the Securities and
Exchange Commission.
Asterisks denote such omission.
 
 
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CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012
 
IN WITNESS WHEREOF, Dyax and STRD have caused this Fourth Amendment to be duly
executed by their authorized representatives under seal, effective as of the
Fourth Amendment Date.

 
DYAX CORP.
                 
By:
/s/ Ivana Magovcevic-Liebisch
   
Name:
Ivana Magovcevic-Liebisch    
Title:
Executive Vice President and      
Chief Business Officer
                 
SIGMA TAU RARE DISEASES S.A.
                 
By:
/s/ Pedro Quintas
   
Name:
Pedro Quintas
   
Title:
Director
                 
SIGMA TAU RARE DISEASES S.A.
                 
By:
/s/ Jose P. Vieira
   
Name:
Jose P. Vieira
   
Title:
Director

Confidential materials omitted and filed separately with the Securities and
Exchange Commission.
Asterisks denote such omission.
 
 
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CONFIDENTIAL DOCUMENT
FINAL MAY 29, 2012

EXHIBIT A
STRD Territory

Original STRD Territory:

Europe:

Albania, Austria, Belgium, Bosnia Herzegovina, Bulgaria, Cyprus, Croatia, Czech
Republic, Denmark, Estonia, Finland, France (Principality of Monaco), Germany,
Greece, Hungary, Iceland, Ireland, Italy (City of Vatican and Republic of San
Marino), Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Macedonia,
Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia,
Slovenia, Spain (Andorra), Sweden, Switzerland, Turkey, United Kingdom

Russia:

Russian Federation, Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan,
Kyrgyzstan, Republic of Moldova, Tajikistan, Turkmenistan, Ukraine, Uzbekistan

First Additional STRD Territory:

Australia
New Zealand

Second Additional STRD Territory:

Latin America:

The following countries of Latin America and the Caribbean: Anguilla, Antigua
and Barbuda, Aruba, Bahamas, Barbados, Belize, Bermuda, Bolivia, British Virgin
Islands, Cayman Islands, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican
Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras,
Jamaica, Montserrat, Netherlands Antilles, Nicaragua, Panama, Paraguay, Peru,
Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname,
Trinidad and Tobago, Turks and Caicos Islands, Uruguay, Venezuela.

Confidential materials omitted and filed separately with the Securities and
Exchange Commission.
Asterisks denote such omission.

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