EXHIBIT 10.12
AGREEMENT
between Stiftelson Industrifonden ("Industrifonden") and Esperion AB, Reg.
No. 556557-5569 ("the Company") concerning a loan for the development of
the protein Apolipoprotein ApoA-Im, a substance having medicinal
properties.
Recitals
On August 11, 1998, the Company applied to Industrifonden for funding of a
project for the development of recombinant production, pure preparation,
and clinical testing of apolipoprotein, ApoA-Im, for the treatment of human
cardiovascular disease, hereinafter referred to as "the Project". On
September 22, 1998, Industrifonden decided to grant the Company a loan,
subject to a conditional repayment obligation, for implementation of the
Project, with the objectives, time schedule, budget, and other contents set
forth in the Project Plan, attached hereto as Appendix 1, hereinafter
referred to as "the Project Plan". On December 18, 1998, the Board of the
Company decided to carry out the Project in line with the Project Plan,
subject to receipt of funding from Industrifonden on the terms agreed in
this Agreement.
1. Obligations of Industrifonden
Industrifonden will grant a loan of fifty million Swedish kronor (SEK
50,000,000) to the Company on the terms set forth in this Agreement for
implementation of the Project in accordance with the Project Plan.
2. Obligations of the Company
Industrifonden's obligations pursuant to this Agreement are conditional
upon the following: The Company shall
(i) make available to the Project the staff, capital, and the
other financial resources and intellectual property rights, including
patents and know-how, as well as the other resources which, in addition to
Industrifonden's funding, are necessary to carry out the Project in
accordance with the Project Plan;
(ii) enter into agreements with each of the interested parties
specified in the Project Plan, largely on the terms stated therein, to the
effect that each interested party will make available to the Project the
resources specified in (i) above, one copy of each such agreement to be
supplied to Industrifonden;
(iii) immediately notify Industrifonden if funding for the Project
or similar purposes is being sought or has been obtained from another public
body;
(iv) principally carry out the Project, and any manufacturing that
may result from the Project, in Sweden; and
(v) refrain from making any substantial changes in the content or
emphasis of the Project, from interrupting or abandoning the Project, or
substantially extending the
time schedule or restricting expected resources without first obtaining
Industrifonden's prior written consent thereto.
(vi) Should the Company request Industrifonden's consent, it is
incumbent on Industrifonden to notify the Company of its decision without
undue delay.
3. Disbursement and reduction of payment
(a) Disbursement by Industrifonden of sums pursuant to Article 1 above
shall at all times be conditional on fulfillment of the following:
(i) The Company has fulfilled its obligations pursuant to
Article 2 and has supplied Indutrifonden with copies of the
agreements specified in Article 2(ii);
(ii) the Company has submitted a report pursuant to
Article 9 not earlier than three months and not later than twenty
days prior to the desired time of payment;
(iii) the Project has not been charged with costs incurred
prior to January 1, 1999;
(iv) the Project is largely proceeding in accordance with
the Project Plan or with the amendments to the Project Plan
permitted by Industrifonden pursuant to Article 2(v);
(v) capital and other resources have been supplied to the
Company at least at the rate stipulated in the Project Plan, and
other aspects of Project funding have not deteriorated in any
material respect;
(vi) advancement of the Project according to plan may be
regarded as reasonably assured, giving due consideration to
developments in the Company's financial status and intellectual
property rights; and
(vii) there are prospects of the Project achieving
satisfactory results within a reasonable time, giving due
consideration to any material changes in technical, commercial or
market conditions.
(b) Provided all the aforementioned conditions have been fulfilled, sums
pursuant to Article 1 above shall be disbursed at the Company's request, in
eight installments as follows:
(1) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 1 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total thirteen million kronor
(SEK 13,000,000), the earliest date of disbursement being March 30, 1999,
however;
(2) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 2 of the Project Plan has been completed and Project costs to
date from January 1, 1999
2
have been shown to total twenty-two million five hundred thousand kronor
(SEK 22,500,00), the earliest date of disbursement being August 15, 1999,
however;
(3) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 3 of the Project Plan has been completed and Project costs to
date from January 1, 199 have been shown to total thirty-five million
kronor (SEK 35,000,000), the earliest date of disbursement being October
15, 1999, however;
(4) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 4 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total forty-seven million five
hundred thousand kronor (SEK 47,500,000), the earliest of date of
disbursement being December 15, 1999, however;
(5) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 5 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total sixty million kronor
(SEK 60,000,000), the earliest date of disbursement being January 15, 2000,
however;
(6) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 6 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total seventy-one million five
hundred thousand kronor (SEK 71,500,000), the earliest date of disbursement
being February 15, 2000, however;
(7) Six million five hundred thousand kronor (SEK 6,500,000) will be disbursed
when Stage 7 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total eighty-three million
kronor (SEK 83,000,000), the earliest date of disbursement being April 30,
2000, however;
(8) Four million five hundred thousand kronor (SEK 4,500,000) will be disbursed
when Stage 8 of the Project Plan has been completed and Project costs to
date from January 1, 1999 have been shown to total ninety-five million five
hundred thousand kronor (SEK 95,500,000), the earliest date of disbursement
being June 15, 2000, however.
(c) If the Project is substantially delayed in comparison with the Project
Plan, Industrifonden shall, as a consequence, be entitled to make
reasonable adjustments in the payment plan in relation to amounts
payable and payment dates following consultation with the Company.
4. Interest
Interest shall be payable at an annual rate of seventeen (17) percent on
principal amounts from time to time outstanding. Accordingly, accrued
interest of 9.5 percent shall be notified and paid each calendar quarter in
arrears on June 30, September 30, December 30 and March 30, the first
payment being made on June 30, 1999. The remaining interest of 7.5 per
cent will be capitalized quarterly in arrear and will then be added to the
principal amount.
5. Interest on arrears
3
In the event of any delay in making due payment of principal or interest,
annual interest on arrears shall be payable on the entire sum of principal
or interest due to Industrifonden from the due date and for as long as the
delay in payment continues, computed at the Swedish Riksbank discount rate
in force from time to time, with the addition of eight (8) percentage
points.
6. Repayment for lower costs
If the total amount disbursed by Industrifonden pursuant to the provisions
of Article 3 above is greater than fifty (50) percent of the final total
Project costs, the Company shall repay the excess amount to Industriofunden
immediately the final Project costs have been determined.
7. Repayment
The Company shall repay the loan disbursed by Industrifonden plus
capitalized interest as follows:
Installments of principal shall be repaid once a year on December 30,
starting the year 2004, the percentages of loan plus capitalized interest
repayable each year being as follows:
20% 2004
20% 2005
20% 2006
20% 2007
The remainder of the loan disbursed plus capitalized interest shall be
repaid to Industrifonden by the Company on December 30, 2008.
The Company is entitled to make premature repayment of all or part of the
loan plus capitalized interest.
8. Forgiveness
Industrifonden may forgive all or part of the Company's debt if, in light
of information presented by the Company, Industrifonden finds that the
results achieved by the Project - notwithstanding its implementation in
accordance with the Project Plan - are obviously not at all, or are only
partly, capable of being used commercially by the Company because the
intended technical results have not been achieved, or because the
commercial or market conditions have materially changed. A further
condition for forgiveness is that the financial and other contributions the
Company has promised or otherwise agreed it would receive from the
interested parties specified in the Project Plan have been made and have
not been repaid or rescinded.
However, Industrifonden is under no obligation to consider the possibility
of forgiving the loan if an application for forgiveness has been made
following occurrence of an event constituting grounds for termination.
4
Refusal by Industrifonden to disburse sums on the grounds that the
conditions set forth in Article 3 (a) have not been fulfilled shall not
constitute grounds for forgiveness.
If the Project Plan contains a number of sub-projects, Industrifonden's
consideration of forgiveness will involve assessment of overall results.
9. Reports
The Company shall, of its own accord, submit brief written reports to
Industrifonden prior to disbursement pursuant to Article 3. These reports
shall contain an account of technical and financial progress made by the
Project in relation to the Project Plan, an up-to-date assessment of the
market conditions relating to the Project, and an account of benefits
derived, or expected to be derived, from the Project. The report shall
also state whether the Company intends to make use of the future payments
set forth in Article 3 (b).
Within thirty (30) days of the end of the preceding quarter, the Company
shall also, of its own accord, submit a report to Industrifonden regarding
the earnings, balance sheet and liquidity position until such time as this
Agreement terminates. These reports shall also contain the information
stipulated in the first paragraph above, together with an assessment of the
market conditions relating to the Project.
The Company shall also, of its own accord, supply Industrifonden with
numbered minutes of board meetings, and material on which the board has
based its decisions, as well as audited annual financial statements and,
where applicable, interim reports.
10. Involvement of the board, right of scrutiny and accounting
A person appointed by Industrifonden shall be offered the opportunity to
participate in meetings of the board of the Company. Notice of meetings,
agenda, minutes and other documents concerning the board's deliberations
shall be supplied to Industrifonden at the same time as they are received
by the Company's board members.
In addition, a person appointed by Industrifonden (e.g., an authorized
public accountant) shall be entitled during the term of this Agreement to
monitor the business of the Company during normal office hours, showing due
consideration to the business conducted by the Company, by meeting Company
representatives and shall be allowed access to documents capable of
providing information on the technical and financial status of the Company
and also be allowed access to the Company's book-keeping and other
documents in order to ascertain that the Company is fulfilling its
obligations towards Industrifonden pursuant to this Agreement.
The Company shall separately account for income and expenses pertaining to
the Project.
11. Confidentiality/publicity
5
Any person at Industrifonden who has been involved in matters concerning
grants or other support within the foundation's sphere of operations may
not, without authorization, divulge any information he has thereby received
as to business or operating conditions (SFS 1979:631). However, the
Company accepts that Industrifonden may publish general information about
its participation in the Project.
The Company is aware that Industrifonden wishes its participation in the
Project to be given publicity in annual reports, press releases, interviews
etc.
12. Transfer of Agreement etc.
The Company's obligations and rights pursuant to this Agreement may not,
wholly or in part, be transferred to another party unless Industrifonden
has approved the transfer and the transferee has entered into an agreement
with Industrifonden in place of this Agreement.
Except as provided by the Project Plan, the Company may not, without
Industrifonden's prior written consent, enter into any agreement whereby
the results of the Project or part thereof are transferred or rights
thereto are granted, wholly or in part.
13. Termination of the Agreement with immediate effect
Industrifonden is entitled to terminate all or part of this Agreement with
immediate effect if the Company:
(a) materially fails to fulfill its obligations pursuant to this Agreement
and fails to remedy such failure within a reasonable time of complaint
of said failure;
(b) supplies or has supplied inaccurate or misleading information of
relevance to Industrifonden's assessment when entering into this
Agreement or when disbursing sums pursuant to the provisions of
Article 1 above;
(c) uses funds disbursed by Industrifonden for purposes other than the
Project;
(d) interrupts, abandons or make material changes in the content or
emphasis of the Project, or substantially extends the time schedule or
restricts expected resources for implementation of the Project without
Industrifonden's prior written consent;
(e) transfers, wholly or in part, its obligations and rights pursuant to
this Agreement without Industrifonden's prior written consent;
(f) goes into liquidation, is declared bankrupt, commences negotiations
with a creditor concerning a composition, or may be assumed to be
insolvent as a consequence of distrait, suspension of payments or
other circumstances.
If the Agreement is terminated by Industrifonden, it shall immediately
cease to apply in therespects decided by Industrifonden. In such case,
loan sums disbursed, plus capitalized interest, plus accrued interest,
minus repayments made before such time pursuant to this Agreement, shall be
deemed due for immediate payment.
6
If the Company has applied for forgiveness, a period of grace shall be
granted until such time as the question of forgiveness has been decided,
provided that Industrifonden is of the opinion that there would appear to
be grounds for granting forgiveness pursuant to Article 8. Interest
pursuant to Article 4 will be payable during the period of grace.
14. Term of the Agreement
This Agreement enters into force on the date of signature hereof by both
parties and shall remain valid until the Company has fulfilled all its
obligations pursuant to the Agreement.
15. Disputes
Any dispute arising out of or in connection with this Agreement shall be
settled by arbitration in accordance with the Rules of the Arbitration
Institute of the Stockholm Chamber of Commerce. The arbitration
proceedings shall take place in Stockholm, and shall be conducted in the
Swedish language.
_________________
This Agreement has been executed in two (2) counterparts, of which the
parties have taken one each.
Xxxxxxxxx, Xxx 00, 0000 Xxxxxxxxx, May 18, 0000
XXXXXXXXXX XXXXXXXXXXXXXX XXXXXXXX XX
---------------------------------- -----------------------
Lars Ojefors Xxxxx X. Xxxxxx
---------------------------------- -----------------------
Ake Oshn Jonas Xxxxxxxx Xxxx Ageland
7
Page 1 of 12
Project plan: Recombinant Apolipoprotein A-IMilano phospholipid complex
(rApoA-IM/PL) in the treatment of atherosclerosis diseases
Background
----------
Esperion AB, Solna, Sweden (Organisationsnummer: 556557-5569), a wholly-owned
subsidiary of Esperion Therapeutics, Inc., Ann Arbor, Michigan, USA (Federal
identification number. 00-0000000), is committed to developing a recombinant
drug in the treatment of atherosclerosis (apo) A-IMilano phospholipid complex.
Both Esperion AB and Esperion Therapeutics, Inc. (collectively Esperion) were
founded in 1998. The main stockholders of Esperion are Oak Investment Partners,
Westport, Connecticut, USA, TL Ventures, Wayne, Pennsylvania, USA, and
HealthCap, Stockholm, Sweden. The CEO of Esperion Therapeutics, Inc. is Xxxxx
Xxxxxx, formerly of Xxxxxx-Xxxxxxx, Xxxxx-Xxxxx. The CEO of Esperion AB is Hans
Ageland, formerly of Pharmacia & Upjohn.
Esperion Therapeutics, Inc. acquired the patents and the rights to pursue the
project from Pharmacia & Upjohn in mid-1998. Pharmacia & Upjohn has the option
to co-develop the product outside North-America after proof of principle has
been accomplished by Esperion in Phase-2 clinical studies. The holders of these
contract agreements are Esperion Therapeutics, Inc. and Pharmacia & Upjohn.
Esperion plans to co-develop the product after Phase-2 results have become
available, depending on the significance of the clinical studies and the
composition of the company at that time. Besides the contracts with Pharmacia &
Upjohn, Esperion retains the discretion to find and negotiate, on commercially
reasonable terms, with partner(s) regarding the transfer and grant of rights to
the Project or Product, which will not require the consent of the Swedish
Industrial Development Fund (SIDF) under section 12, paragraph 2 of the Loan
Agreement. However, Esperion has an obligation, except to the extent prohibited
by the terms of any confidentiality agreements between Esperion and such
proposed partner, to inform SIDF about major transfers and to provide
documentation enabling SIDF to evaluate the transfer or grant of rights and
provide SIDF with the opportunity to comment within fifteen days from the date
the information and documentation was sent.
Page 2 of 12
Medical Rationale:
-----------------
Coronary heart disease is the main killer in the Western world and its
prevalence is increasing in the former under-developed countries. The main
reason for coronary heart disease is atherosclerosis. Accumulation of
cholesterol in the arterial wall causes atherosclerosis. Cholesterol
accumulation in the vessel wall is regulated by a) delivery of cholesterol from
plasma, b) retention of cholesterol in the vessel wall and c) removal of
cholesterol from the wall. Present treatment modalities, such as with statins,
relate to the reduction of the LDL cholesterol and delivering of cholesterol to
the artery. However, cholesterol present in cells of the vessel wall cannot be
catabolized. The degree of accumulation is therefore dependent on the
cholesterol removal mechanism. Cholesterol from peripheral cells are removed
from the vessel wall, transported in plasma and delivered to the liver for
excretion as bile after hydroxylation in a process called "the-reverse
cholesterol transport" (RCT). High levels of HDL and apo A-I are known to
protect humans from coronary heart disease. Causality of the protective effect
of apo A-i to atherosclerosis has further been established in experimental
animal studies.
The main metabolic and structural component of RCT is apo A-I, a 243 amino acid
protein, which together with cholesterol and phospholipids comprise high-density
lipoprotein (HDL). A variant of this protein, apo A-IMilano has an arginine to
cysteine substitution in position 173 and has shown higher efficiency than the
natural protein for cholesterol removal from cells. The aim of the project is
to augment the natural defense system of RCT by infusing apoA-IMilano completed
to a phospholipid carrier. By accelerated removal of cholesterol from the
vessel wall atherosclerosis disease progression can be prevented and established
atherosclerosis regressed, thereby postponing or all together avoiding clinical
presentations of cardiovascular disease. Target patient groups are those with
compromised RCT or those that for any reason are dependent on an efficient RCT
system to maintain cholesterol homeostasis.
The Milano-variant. of apoA-I was originally detected in Italian descendents in
Limone sul Garda by Xxxx. Xxxxxxx and colleagues, University of Milan, in the
late 1970s (Xxxxxxxxxxxx and Sirtori. J Chin Invest 1980;66:901-7). Carriers
are provided protection from coronary heart disease despite having only one-
third of the apoA-I protein concentration compared to what normally is found,
supporting an increased activity of the Milano variant compared to the
Page 3 of 12
common type of protein. Experimental studies in animals have shown that the
complex of rApoA-IM and phospholipid (rApoA-I/PL complex) can prevent neointima
formation after denudation and perivascular manipulation of arteries (Ameli et
al., Circulation 1994 Oct; 9K4):19354 1, Soma et al., Circ Res 1995 Mar;
76(3):405-11). The rApoA-I/PL complex has also shown significant efficiency in
preventing atherosclerosis development and regressing atherosclerosis in
atherosclerosis-prone mice, i.e. apoE knock out mice (Shah et al., Circulation
1998 Mar 3; 97(8):7M5). For details, see enclosure 1. The complex also restores
deteriorated arterial endothelial function (data on line, Esperion). Further
biological explanation for the rationale of the recombinant development is
provided below.
Production characterization and quality assessment
--------------------------------------------------
The quality of the apoA-IMilano production will be determined according to
specifications for isolation, purification, and final product formulation.
Characterization and assessment will follow conventional pharmaceutical
standards for biotech production in Europe and the US. Please note that the
pharmaceutical industry is a highly regulated industry.
Relation between Esperion AB and Esperion Therapeutics, Inc.
------------------------------------------------------------
Esperion AB generally constitutes the development arm of Esperion. Esperion
Therapeutics, Inc. is generally the research arm (discovery and exploratory) and
head office base of the company in Ann Arbor, Michigan, USA. Esperion AB and
Esperion Therapeutics, Inc. will collaborate on the project pursuant to an
operating agreement between the companies (see agreement dated March 31, 1999)
which allows Esperion AB full use of the proprietary rights of apoA-IMilano.
New findings, results and patents are, according to the same contract, to be
transferred and owned exclusively by Esperion Therapeutics, Inc.
Transactions between Esperion AB. and Esperion Therapeutics Inc. related to the
project will on all occasions be on "an arm's length basis" and based on current
market terms. In accordance with the Project plan, activities have already
started as of January 1, 1999, and will continue over the next 15 months.
Page 4 of 12
Esperion AB and Swedish Industrial Development Fund
---------------------------------------------------
Project investments and the draw-downs of the loan from the Swedish Industrial
Development Fund (SIDF) will follow 8 milestones (see below) and include
establishing the Esperion AB in Solna Sweden. Biotech development and
production of the recombinant protein according to GLP (Good Laboratory
Procedure), for toxicology studies in animals, and according to GMP (Good
Manufacturing Procedure), for studies in humans, will take place primarily in
Sweden and be supported by Esperion AB. The clinical component of the project
will include method developments to monitor efficiency of administration of the
drug complex. This includes RCT monitoring and other related metabolic
analysis. These include cell assays to monitor efflux cholesterol capacity from
cells, bile acid and feces analysis for cholesterol production excretion, and
monitoring of de novo cholesterol synthesis by serum analysis. Techniques to
monitor effects of treatment on cardiovascular structure-function will also be
developed. Furthermore, we will investigate new methods to identify individuals
with compromised RCT and individuals that are prone to be good responders to apo
A-IM treatment. The Project's fund milestone with SIDF comprises completion of
the IND application (Investigative New Drug) to the FDA (Food and Drug
Administration) in the USA and/or the corresponding procedure in Europe (EMEA,
European Medicines Evaluation Agency), which is planned to occur in June 2000.
Page 5 of 12
Description, reports, and tentative dates of milestones and the corresponding
loan amounts in Swedish kronor (SEK).
1st Milestone.
--------------
Reestablishing the production facility in Strangnas, Sweden. The apolipoprotein
A-IM is produced in a multi-step process including fermenting, chromatography
separation, and filter separation. The facility needs to be reconfigured for
production of this specific protein.
Establishing Esperion AB and its office in Solna, Sweden. The milestone
documentation will be a technical report which include the "water-test" of the
facility and is planned for late March 1999.
SEK 6.5 million.
2nd Milestone.
--------------
The milestone is the production of 1000 g protein in solution, according to
batch protocol and product specification. It will be considered reached after
presentation of a technical report specifying the production of the batches.
This is planned for August 1999.
SEK 6.5 million.
3rd Milestone.
--------------
The result of the acute toxicology study. This is the first step in several
toxicology studies where possible adverse and toxicological effects of the
protein are being evaluated. One purpose of the study is to delineate the
maximum tolerated dose. A rising dose protocol will be implemented until the
appearance of toxicological effects. Pharmacokintetic studies then follow,
relating dose to the blood level of recombinant apoA-IM protein. The study will
be performed by an external laboratory, possibly Covance Ltd, Leeds, UK.
The milestone is concluded with a conventional report from the contract
laboratory according to established guidelines. This is planned for October
1999.
SEK 6.5 million.
Page 6 of 12
4th Milestone.
--------------
Manufacturing of the product in accordance with current GMP standard. One to
three of the batches will be produced, according to the time plan, before
completion of the 4th milestone. Further batches to provide material for the
clinical testing Phase-1 and Phase-2a will be produced in close connection with
the three first batches.
The milestone will be documented in a written report describing the production
process and characterization/specification of the final product. Planned to
complete by December 1999.
SEK 6.5 million.
5th Milestone.
--------------
Toxicology studies supporting clinical Phase-I and Phase-2 studies. The studies
will be performed in two species (rat and monkey). It will be performed by an
external toxicology organization. Their final report will constitute the basis
of the milestone. This report is planned for January 2000.
SEK 6.5 million.
6th Milestone.
--------------
Appropriate cell culture models, assay systems, will be developed to ensure
rigorous evaluation of apo A-IM production batches. Furthermore, genomics data
collection and patient sample testing will be performed in order to minimize the
clinical trial populations/protocols. Documentation describing the
investigations will be presented in summary form by February 2000.
SEK 6.5 million.
7th Milestone
-------------
Development of methods and concepts to analyze and illustrate metabolic and
vascular effects of rLpA-IM treatment. Metabolic analysis will focus on
variables related to reverse cholesterol transport and associated effects of
rLpA-IM treatment including endothelial function and specific inflammation
parameters, e.g. Tumor Necrosis Factor-alpha and Vascular Cell Adhesion
Molecules. Vascular methods to analyze and monitor arterial structure-function
are being
Page 7 of 12
developed and will be applied to detect systemic and local vascular effects of
rLpA-IM treatment.
Documentation of the milestone will be in the form of a summary report planned
for April 2000.
SEK 6.5 million.
8th Milestone.
--------------
IND (Investigative New Drug) Application to the FDA (Food and Drug
Administration), USA, and/or the corresponding procedure in Europe, EMEA
(European Medicine Evaluation Agency). Biotech product applications in Europe
follow the centralized procedure whereby the applicant may propose the country
that will -evaluate the application. Planned to complete by June 2000.
SEK 4.5 million.
General comment: The milestones are presented in a sequential way. In reality,
they are, to a considerable degree, prepared and executed in parallel.
Investments in the project are firstly done by Esperion and then by the SIDF
loan, the latter investment never exceeding the amount of the former.
Esperion AB
/s/ Xxxxx X. Xxxxxx
---------------------
Xxxxx X. Xxxxxx
/s/ Hans Ageland
---------------------
Hans Ageland
Page 8 of 12
Enclosure 1.
Relevant non-clinical data
Anti-atherosclerosis: The object of this study (Shah et. al , Circ. 1998) was
--------------------
to test the hypothesis that rApoA-IM/PL would inhibit aortic atherosclerosis
induced by cholesterol feeding in atherosclerosis-prone mice. ApoE deficient
mice received injections of rLpA-IM/PL every other day for 5 weeks (40 mg/kg),
resulting in a significant inhibition of atherosclerosis development Refer to
Study Summary Table 1.
---------------------------------------------------------------------------------------------------------
Study Summary Table 1. Inhibition of atherosclerosis development in apoE KO mice.
---------------------------------------------------------------------------------------------------------
Shah et al. Control Mice Treated Mice*
-------------------------------------------------------------------------
20 weeks 25 weeks 25 weeks
(n = 8) (n = 7) (n = 15)
---------------------------------------------------------------------------------------------------------
Aortic atherosclerosis 11 + or - 1 17 + or - 5 11 + or - 1
---------------------------------------------------------------------------------------------------------
Lipid content 22 + or - 8 32 + or - 6 13 + or - 8
---------------------------------------------------------------------------------------------------------
Macrophage content 10.8 + or - 2 13.2 + or - 6 5.8 + or - 2.9
---------------------------------------------------------------------------------------------------------
*18 injections of rApoA-I/PL per animal during weeks 20-25
+ or - plus or minus
Anti-restenosis (1): the object of this study (Amelie et al, Circulation, 1994)
-------------------
was to determine whether rApoA-IM/PL confers vascular protective effect after
balloon injury, i.e. prevents restenosis. Cholesterol-fed rabbits received
doses of 40 mg of rApoA-IM/PL complex every other day for 5 days before and 5
days after balloon injury. The rApoA-IM/PL complex significantly reduced
intimal thickening and macrophage content after balloon injury, compared with
controls. Refer to Study Summary Table 2.
Page 9 of 12
---------------------------------------------------------------------------------------------------------
Study Summary Table 2.
Prevention of arterial neointima formation after balloon injury in rabbits.
---------------------------------------------------------------------------------------------------------
Control PL RApoA-IM/PL complex
Ameli et al. (n = 4) (n = 8) (n = 8)
---------------------------------------------------------------------------------------------------------
Intimal thickness (mm/2/) 1.69 + or - 0.43 1.14 + or - 0.38 0.49 + or - 0.29
---------------------------------------------------------------------------------------------------------
Intima-to-media ratio 2.1 + or - 0.1 1.5 + or - 0.5 0.7 + or - 0.2
---------------------------------------------------------------------------------------------------------
Macrophage content Not defined 59.4 + or - 12.5% 25.3 + or - 17%
---------------------------------------------------------------------------------------------------------
+ or - plus or minus
Anti-restenosis (2): The object of this study (Soma et al, Circulation 1995)
-------------------
was to evaluate the effect of rApoA-IM/PL on neointimal formation induced by
perivascular manipulation in rabbits, i.e. application of a collar around the
carotid artery. In a study similar in design to the rabbit study above, 40
mg/kg infusions of rApoA-IM/PL were given at 5 occasions from day 5 before
collar application to 5 days after collar application. Treatments resulted in a
decrease in intima proliferation. Refer to Study Summary Table 3.
Page 10 of 12
---------------------------------------------------------------------------------------------------------
Study Summary Table 3.
Prevention of carotid artery neointima formation after perivascular collar
Manipulation rabbits.
---------------------------------------------------------------------------------------------------------
Soma et al. Controls PL rApoA-IM/PL
(n = 5) (n = 5) (n = 5)
---------------------------------------------------------------------------------------------------------
Intima:media ratio 0.63 + or - 0.11 0.50 + or - 0.14 0.25 + or - 0.19
---------------------------------------------------------------------------------------------------------
Smooth muscle proliferation -
intimal tissue 68.0 + or - 27.0 61.0 + or - 28.0 29.0 + or - 23.0
---------------------------------------------------------------------------------------------------------
Smooth muscle proliferation -
Medial tissue 116 + or - 18 127 + or - 26 109 + or - 19
---------------------------------------------------------------------------------------------------------
+ or - plus or minus
Page 11 of 12
Enclosure 2.
Relevant scientific references of the project:
Xxxxxxxxxxxx, G., X. Xxxxxxx, X. Xxxxxxx, K Weisgraber and X. Xxxxxx. "A-
IMilano apoprotein: Decreased high density lipoprotein cholesterol levels with
significant lipoprotein modifications and without clinical aherosclerosis in an
Italian family." J. Clin. Invest. 66: 892-900, 1980.
--
Xxxxxxxxxxxx, G, X. Xxxxxxx, X. Xxxxxxxxxxxxxx and X. Xxxxxxx. "Relation
between the HDL Apoproteins and Al isoproteins in subjects with the AIMilano
abnormality." Metabolism 30 (5): 502-509,1981.
--
Xxxxxxxxxxxx, G., T. Frosi, X. Xxxxxxx, X. Xxxxxxxxxxxxxx and X. Xxxxxxx. "High
density lipoprotein-3 heterogeneity in subjects with the apo-AIMilano variant.
J. Biol. Chem. 257 (17): 9926-9930,1982.
---
Gualandri, X., X. Xxxxxxxxxxxx, X. Xxxxxxx, X. Xxxxxxxxxxxxxx, X. Xxxxxx, X.
Xxxxxxx and X. Xxxxxxx. "AIMilano apoprotein identification of the complete
kindred and evidence of a dominant genetic transmission." Am. J. Hum. Genet.
37: 1083-1097, 1985.
--
Xxxxxxxxxxxx, G., X. Xxxxxxx, X. Xxxxxxx, X. Xxxxxxxxx, X. Xxxxxx, X. Xxxxxxxx
and X. Xxxxxxx. "Relationship of the phenotypic expression of the AIMilano
apoprotein with plasma lipid and lipoprotein patterns." Atherosclerosis 58:
--
159-174, 1985.
Gualandri, V., X. Xxxxxx, X. Xxxxxxx, X. Xxxxxxxxxxxx and X. Xxxxxxx. "Familial
associations of lipids and lipoproteins in a highly consanguineous population:
the Limone sul Garda study." Metabolism 34(3): 212-221, 1985.
--
Xxxxxxxxxxxx, G., X. Xxxxxxx, X. Xxxxxxxxxxxxxx, X. Xxxxxx and X. Xxxxxxx.
"Apolipoprotein AIMilano: accelerated binding and dissociation from lipids of a
human apolipoprotein variant." J. Biol. Chem. 260(30): 16321-16325, 1985.
---
Xxxxxxxxxxxx, G., X. Xxxxxxxxx, X. Xxxx, X. Xxxxxxx, X. Xxxxxxxxxx, X. Xxxxxx,
X. Xxxx, X. Xxxxxxx and X. Xxxxxxx. "Apolipoprotein AIMilano: correlation
between high density lipoprotein subclass distribution and triglyceridemia."
Arteriosclerosis 7: 426-435, 1987.
-
Xxxxxxxxxxxx, G., X. Xxxxxxxxx, X. Xxxx, X. Xxxxxxx and X. Xxxxxxx. "Structure
and functionality of the HDL system in carriers of the Apolipoprotein AIMilano
mutant." Atherosclerosis VIII, 1989.
Xxxxxxxxxxxx, G., X. Xxxxxxxxx, X. Xxxx, X. Xxxxxxxxxxxxxx, X. Xxxxxxx and X.
Xxxxxxx. "Apolipoprotein AIMilano: disulfide-linked dimers increase high
density lipoprotein stability and hinder particle interconversion in carrier
plasma." J. Biol. Chem. 265(21): 12224-12231, 1990.
---
Page 12 of 12
Calabresi, L., X. Xxxxxxxxxx, X. Xxxxxxxxxxxxxx, X. Xxxx, T. Marukami, X.
Xxxxxxx and X. Xxxxxxxxxxxx. "Increased postprandial lipemia in Apo AIMilano
carriers." Arteriosclerosis and Thrombosis 13(4): 521-528, 1993.
--
Bekaert, E., X. Xxxxxxxxx, X. Xxxxxx-Xxxxxx, X. Xxxxxxxxxxxx and X. Xxxxxxx.
"Apolipoprotein AIMilano: sex-related differences in the concentration and
composition of apoA-I- and apoB-containing lipoprotein particles." J. Lipid
Res. 34: 111-123, 1993.
--
Roma, P., R.E. Xxxxx, X.X. Xxxx, X. Xxxxx, X.X. Xxxx, X. Xxxxxxxxxxxx, X.X.
Xxxxxxx and X.X. Xxxxxx, Xx. "In vivo metabolism of a mutant form of
apolipoprotein A-I, apo A-IMilano, associated with familial
hypoalphalipoproteinemia." J. Clin. Invest. 91: 1445-1452, 1993.
--
Calabresi, L., X. Xxxxxxx, X. Xxxxxx, X. Xxxxxxxx, G. Palm, X. Xxxxxxxxx, X.
Xxxxxxxxxxx, X. Xxxxxx, A. Karkstrom, T. Sejlitz, H. Ageland, X. Xxxxxxx and X.
Xxxxxxxxxxxx. "Molecular characterization of native and recombinant
apolipoprotein A-IMilano dimer." J. Biol. Chem. 269(51): 32168-32174, 1994.
---
Chiesa, G., X.X. Xxxxxxxx, X. Xxxxxxxxxxxx, X.X. Xxxxxxxx, X. Xxxxx, X.X. Xxxxx,
X.X. Xxxxxxx, X. Xxxxxxxxxxxx and X.X. Xxxxx. "Elevated triglycerides and low
HDL cholesterol in transgenic mice expressing human apolipoprotein A-IMilano."
Atherosclerosis 136: 139-146, 1998.
---
AGREEMENT
1. Parties
1.1. Esperion Therapeutics Inc. 0000 X. Xxxxx Xxxxxx 000 XXX Xxxxx, Xxx Xxxxx,
XX 00000, XXX
1.2. Esperion AB, Reg. No. 556557-5569, Xxxxxxxxxxxxx 000, 000 00 Xxxxx, Xxxxxx.
2. Background
2.1. Esperion AB is a wholly-owned subsidiary of Esperion Therapeutics Inc.
2.2. Esperion AB has decided to enter into a loan agreement with Stiftelsen
Industrifonden ("Industrifonden"), which is enclosed hereto as Appendix 2.2
(the "Loan Agreement"). Under the Loan Agreement, Industrifonden shall lend
Esperion AB SEK 50,000,000 and Esperion AB shall perform a project (the
"Project") in accordance with the project plan enclosed to the Loan
Agreement (the "Project Plan").
2.3. Whereas Esperion Therapeutics Inc. is the owner of the intellectual
property rights necessary for the performance of the Project, the parties
hereto have decided that Esperion AB shall, if the Loan Agreement is signed
by both parties, have full access to the necessary intellectual property
rights on the terms and conditions of this agreement.
3. Intellectual Property Rights
3.1. Esperion Therapeutics Inc. hereby grants Esperion AB right without any
obligation for Esperion AB to pay any remuneration whatsoever to Esperion
Therapeutics Inc. to use any patent, know-how or other intellectual
property rights owned by Esperion Therapeutics Inc. ("Intellectual Property
Right"), which Esperion XX xxxxx necessary for the performance of the
Project in accordance with the Project Plan.
3.2. No title to any of the Intellectual Property Rights shall pass or be
transferred pursuant to this agreement.
3.3. New results, including patents, know-how or any other intellectual property
rights, which are generated from the performance of the Project and which
are based on the Intellectual Property Rights (the "New Results"), shall be
transferred to and owned exclusively by Esperion Therapeutics Inc.
3.4. Esperion Therapeutics Inc. hereby grants Esperion AB the right to use the
New Results for the performance of the Project in accordance with the
Project Plan.
3.5. The rights granted to Esperion AB under section 3.1 and 3.4 above shall
apply until the Project has been finalized in accordance with the Project
Plan.
1
4. Governing law
4.1. This Agreement shall be governed by the laws of Sweden.
This agreement has been executed in three identical counterparts of which the
parties and Industrifonden have taken one each.
Xxxxxxxxx Xxx 00, 0000 Xxxxxxxxx 990518
---------------------------------------- ----------------------------------
Place Date Place Date
ESPERION THERAPEUTICS INC. ESPERION AB
/s/ Xxxxx X. Xxxxxx /s/ Hans Ageland
---------------------------------------- ----------------------------------
Xxxxx X. Xxxxxx Xxxx Ageland
Industrifonden hereby gives its consent to this agreement.
Stockholm, May 19, 1999
STIFTELSEN INDUSTRIFONDEN
/s/ Lars Ojefors
---------------------------------------------------
Lars Ojefors
/s/ Ake Osihn /s/ Jonas Brambeck
-----------------------------------------
Ake Osihn Jonas Brambeck
2
SURETY AGREEMENT
The following Surety Agreement has been entered into this day by and between
Stiftelsen Industrifonden, Registration Number 802009-009, XX Xxx 0000, XX-000
00 Xxxxxxxxx, Xxxxxx ("Industrifonden"), and Esperion Therapeutics Inc., federal
identification number 00-0000000, 0000 X. Xxxxx Xxxxxx, 695 KMS Place, ANN
ARBOR, MI 48 108, USA, ("Esperion Therapeutics").
1.
Esperion Therapeutics Inc. hereby stands surety as for its own debts for the due
performance by Esperion AB, Reg. No. 556557-5569, ("Esperion") of its payment
obligations towards Industrifonden pursuant to the agreement entered into this
day between Industrifonden and Expression, a copy of which is attached as
Appendix 1 hereto.
2.
Without affecting the validity of the surety given by Esperion Therapeutics in
clause 1 above and without limiting the scope and effect of said surety,
Esperion Therapeutics shall be entitled to invoke all Esperion's rights pursuant
to the loan agreement between Industrifonden and Esperion, a copy of which is
attached as Appendix 1 hereto.
3.
This Surety Agreement shall be subject to the laws of Sweden.
4.
Any dispute arising in connection with this Surety Agreement shall be finally
settled by arbitration in accordance with the rules of the Arbitration Institute
of the Stockholm Chamber of Commerce. The arbitral proceeding shall take place
in Stockholm, and shall be conducted in the Swedish language.
_______________________
This Surety Agreement has been executed in two (2) counterparts, of which the
Industrifonden and Esperion Therapeutics have taken one each.
Xxxxxxxxx, Xxx 00, 0000 Xxxxxxxxx, May 18, 1999
STIFTELSEN INDUSTRIFONDEN ESPERION THERAPEUTICS INC.
/s/ Lars Ojefors /s/ Xxxxx X. Xxxxxx
----------------------------------- ------------------------------
Lars Ojefors Xxxxx X. Xxxxxx
