Exhibit
10.28


 


CONTRACT


 


Between Axonyx Europe, with its registered office at bilderdijkstraat
9, 2311 XD Leiden, The Netherlands and NOTOX Safety & Environmental
Research B.V., with its registered office at Hambakenwetering 7, 5231 DD
‘s-Hertogenbosch, The Netherlands.


 


Herewith NOTOX offers to perform a 104-weeks rate carcinogenicity study
with Phenserine tartrate, a compound being developed as a drug for use in the
treatment of Alzheimer’s disease.  The
study will be carried out in accordance with the respective test guidelines
(ICH) and in conformity with the OECD principles for “Good Laboratory
Practice”.


 


The study is based on the following study outline and will in detail
follow the enclosed protocol that was fully accepted by Dr. Black of Hugh E.
Black & Associates, Inc., who acts as the sponsor’s consultant in this
project.


 


Study
outline:


 


104-Weeks
oral gavage carcinogenicity study of Phenserine tartrate in Wistar Han rats.


 


	
  Number of groups:

  	
   

  	
  2 controls and 3 treatments; group housing.

  
	
  Group size:

  	
   

  	
  60 males, 60 females/ main group; 30 health check
  animals: in total 630 animals.

  
	
  Age:

  	
   

  	
  4 weeks at arrival, 6 weeks at start of dosing

  
	
  Administration:

  	
   

  	
  Daily oral gavage for 104 weeks.

  
	
  Observations:

  	
   

  	
  • Clinical
  signs daily, before and 1-2 hours after dosing.

  
	
   

  	
   

  	
  • Viability
  / mortality:  twice daily.

  
	
   

  	
   

  	
  • Weekly
  palpatation for tumours.

  
	
  Body weight / food consumption:

  	
   

  	
  Weekly during first 14 weeks and every 2 weeks
  thereafter; one week pretest.

  
	
   

  	
   

  	
   

  
	
  Ophthalmoscopy:

  	
   

  	
  15 animals / sex / group: pretest and during week
  52.

  
	
  Haematology:

  	
   

  	
  15 animals / sex / group during pretest; all animals
  killed in extremis or at terminal necropsy.

  
	
  Toxicokinetic sampling:

  	
   

  	
  At 3 time points / day at day 1, week 26 and week
  104; 4 TK-samples / sex / group / time point: 216 samples in total.

  
	
  Pathology:

  	
   

  	
  • Full
  necropsy on all animals.

  
	
   

  	
   

  	
  • Full
  histopathology on unscheduled deaths, both control groups and high dose group
  animals.  Limited histopathology on
  low and mid dose group animals killed after two years.

  



 


Toxicokinetic assessment and evaluation.


 


	
  Costs
  2-years study:

  	
   

  	
  Î  1,045,000.00

  



 


The formulations necessary for daily oral gavage of the test compound
will weekly be prepared at NOTOX.  The
formulations will be analysed according to the schedule, depicted in the study
protocol.  Blood samples taken at three
time points on three days during the study will be analysed using LC-MS/MS in
NOTOX’ bio-analytical department.  After
toxicokinetic assessment the evaluation will be included in the study report.


 


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Analytical
Chemistry:


 


Formulation Analysis


 


	
  •

  	
   

  	
  Implementation and validation of an analytical
  method on HPLC (includes determination of linearity, detection limit,
  repeatability of injections and stability tests) for rat oral gavage
  formulations

  	
  Î

  	
  8,500.00

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  •

  	
   

  	
  Analyses: 
  estimated 6 occasions of analysis (Î 1,800.00 / analysis day)

  	
  Î

  	
  10,800.00

  



 


Bio-analysis


 


	
  •

  	
   

  	
  Protocol and report method development and
  validation:

  	
  Î

  	
  5,000.00

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  •

  	
   

  	
  Method development and validation in one matrix

  	
   

  	
   

  
	
   

  	
   

  	
  • parent compound only; expected work: 3-7 weeks

  	
   

  	
   

  
	
   

  	
   

  	
  • costs per week: Î 6,250.00

  	
   

  	
   

  
	
   

  	
   

  	
  • Assuming 5 weeks of development/validation:

  	
  Î

  	
  31,250.000

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  •

  	
   

  	
  Analysis of initially 216 rat samples (from dose
  group animals only; price per sample Î 90.00):

  	
  Î

  	
  19,440.00

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  •

  	
   

  	
  Protocol and report sample analysis:

  	
  Î

  	
  5,000.00

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Estimated costs analytical chemistry:

  	
  Î

  	
  79,990.00

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Total
  costs (excl. V.A.T.):

  	
  Î

  	
  1,124,990.00

  



 


 


Remarks:


 


•                                          The amount of
test substance needed to carry out the study will be determined in consultation
with the sponsor.


•                                          The
prices include sampling and storage for formulation and bio-analysis.


•                                          Reserve
samples of the test and control articles (2 ml) will be taken at initiation and
after 6 months, 12 months, 18 months and at the end of the study and will be
retained until completion of the in-life phase,


•                                          30
Extra animals for health check by serology will be added to the study on NOTOX’
costs.


•                                          All
data and the final report will be submitted to the sponsor as a PDF file for
possible inclusion in an electronic submission to regulatory agencies.


•                                          Costs
are calculated assuming regular protocol and report formats.  Special requests for protocol (study design)
and report format may lead to additional costs.


•                                          Interim
results (see protocol for frequency) and a draft report will be provided
without additional costs.


 


2

















 


Timelines:


 


•                                          The
method development and validation for formulation analysis will be performed
during week 19-21.  The method will be
available then in week 24, 2002.  This
schedule can be met if we have received a completed test substance data sheet,
relevant analytical information, sufficient test substance and necessary
reference compounds in week 17, 2002, at the latest.


•                                          The
method development and validation for bio-analysis will be started in week 30,
2002, assuming the necessary information and/or substances have been provided
by the sponsor in week 28, 2002, at the latest.  The validation report will be issued then at least 4 weeks before
the start of the 2-years rat study.


•                                          For
the carcinogenicity study the rats will arrive at NOTOX in the third week of
October 2002.


•                                          After
allocation and acclimitization the study will start in the first week of
November 2002.


•                                          At
the end of the study the remaining animals will be sacrificed and subjected to
pathology in November 2004.


•                                          Friday
29th April 2005 a non-QA-audited, finalised report on the
carcinogenic potential of Phenserine tartrate in rats 14 days after receipt of
all comments of NOTOX.


 


Terms of
payment and additional remarks:


 


•                                          Payment
for the carcinogenicity study should be carried out in eight terms.  The first installment of 30% of the total
estimated costs will be at acceptance of this contract.  The next installments of six times 10% each
will be divided over the project and the last 10% should be paid at receipt of
the draft report.


•                                          Payments
should be made within 14 days after the date mentioned in the respective
invoices.


•                                          By
signing this contract the sponsor also agrees to NOTOX’ general terms and
conditions.


 


Premium
–penalty settlement:


 


•                                          For
delivery of the final report before the reference date (reviewing time + 14
days after 29th April 2005) NOTOX will receive a premium amount of €
10,000.00 / week until a maximum of € 40,000.00.


•                                          For
delivery of the final report after this reference date NOTOX will pay a penalty
amount of € 5,000.00/ week until a maximum of € 40,000.00.


•                                          A
penalty will only be accepted if the delay can fully be attributed to
negligence and/or demonstrable falure by NOTOX.


•                                          A
penalty will not be accepted if the delay is caused by one or more of the
following reasons:


• The test
substance is not or not sufficient available during any moment in the study.


• Relevant
information on the analyses, toxicity pattern, etc. of the compound is not
available at NOTOX when needed.


• Unexpected
illness or deaths of rats that significantly damage the progression in the
study.


• A toxicity /
tumour pattern leading to unexpected and significantly more work during
pathology.


• A reviewing
time of the report exceeding the proposed 2 weeks (incl. transfer time).


• Extra
requests during the project that will result into extension of the reporting
period.


• The penalty
clause will not be applicable in case not all payments are received on time.


 


	
  ‘s-Hertogenbosch, 11th April 2002

  	
   

  	
   

  
	
   

  	
   

  	
  For confirmation:

  
	
  NOTOX Safety & Environmental Research B.V.

  	
   

  	
  AXONYX

  



 


 


	
   /s/ Dr.
  R.E.J. ten Berge

  	
   

  	
  /s/ Ir. J.C.M. van der Hoeven

  	
   

  	
  /s/ G.B. Bruinsma, M.D.

  	
   

  
	
  Dr. R.E.J. ten Berge

  	
  Ir. J.C.M. van der Hoeven

  	
  G.B. Bruinsma, M.D.

  
	
  Sales & Marketing Manager

  	
  Managing Director

  	
  Chief Operating Officer

  
	
  Pharmaceuticals

  	
   

  	
   

  



 


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