Exhibit 10.1
SECOND AMENDMENT
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This Second Amendment pertains to the License Agreement (hereinafter the
"License Agreement") effective December 16, 1996 and the First Amendment to the
License Agreement effective December 30, 1999 by and between the MASSACHUSETTS
INSTITUTE OF TECHNOLOGY (hereinafter referred to M.I.T.) and ORASOMAL
TECHNOLOGIES, INC., a subsidiary of Endorex Corporation, (hereinafter referred
to as LICENSEE)
WHEREAS, LICENSEE has pursued diligently the development of the
polymerized liposome technology for both orally and intranasally administered
vaccines and orally administered peptide and protein therapeutics as described
in ATTACHMENT A, but is not yet ready to enter, per the terms of section 3.4,
into clinical trials.
NOW, THEREFORE, inconsideration of the modifications contained herein, the
parties hereby agree:
1. To modify the License Agreement by deleting Paragraph 3.4 in its
entirety and substituting therefore the following:
3.4 On or before January 1, 2006, LICENSEE will enter Phase I
clinical trials or equivalent on the U.S. or other Major Country
for at least one application of the technology described in the
Patent Rights.
2. To modify Sections 4.1c and 4.1d, such that the License Maintenance
Fees due on January 1st in each of the years through, and including,
the year in which the obligation of Section 3.4 is fulfilled, will
be Twenty Thousand Dollars ($20,000).
3. Should LICENSEE enter into Phase I clinical trials on or before the
above January 1, 2006, the license maintenance fee(s) due on any
forthcoming January 1st shall again be Ten Thousand Dollars
($10,000).
All other terms and conditions of the above referenced License Agreement
remain unchanged and in full force and effect.
The Effective Date of this Second Amendment as October 31, 2001.
Agreed to for M.I.T. by: Agreed to for LICENSEE by:
MASSACHUSETTS INSTITUTE OF ORASOMAL TECHNOLOGIES, INC.
TECHNOLOGY
/s/ Xxxx Xxxxxx /s/ Xxxxxxx X. Xxxxx
By___________________________________ By_______________________________________
Xxxx X. Xxxxxx Xxxxxxx X. Xxxxx
Name_________________________________ Name_____________________________________
Director
Technology Licensing Office President/CEO
Title________________________________ Title____________________________________
October 26, 2001 October 29, 2001
Date_________________________________ Date_____________________________________
ATTACHMENT A
Oral Delivery of Peptide/Protein Drugs and Vaccines in Polymerized Liposomes
Progress Report on MIT license #6388
October 31, 2001
In November of 1999, Orasomal Technologies (Orasomal), a subsidiary of
Endorex Corporation, requested a two-year extension under clause 3.4 of its
exclusive license agreement with M.I.T., which stipulates a requirement to enter
into human clinical development with the licensed technology. This extension
will be effective until January 1, 2002. At this time, Orasomal has not yet
entered into clinical trials with the technology and is requesting a further
extension.
Preclinical development
Orasomal and Endorex Corporation have pursued diligently the development
of the polymerized liposome technology for both orally and intranasally
administered vaccines and orally administered peptide and protein therapeutics.
Studies to date have been confined to either peroral and intranasal
administration of vaccines in inbred mice or peroral and intraduodenal
administration of drugs in rats. As Orasomal identifies suitable candidates,
further animal models will be employed in advancing the technology to clinical
development.
Vaccines: Joint venture with Elan.
As mentioned in the progress report of November 1999, Orasomal had
entered into a corporate joint venture with Elan Corporation (Dublin, Ireland)
to develop technology exclusively for human oral or mucosal vaccines. The joint
venture (Innovaccines Corporation) has been operational since January of 1998.
Innovaccines consists of R&D operations in both Dublin, where cellular ligands
for gastrointestinal targeting and process development and scale-up occurs and
in Orasomal headquarters in Illinois, where liposome formulations have been
developed, analyzed, and evaluated in animals.
For purposes of conducting proof of concept human clinical trials,
Innovaccines sought to develop either an orally or intranasally administered
prototype vaccine for tetanus. Successful demonstration of tetanus vaccine
safety and immunogenicity would be followed by further efficacy trials with
tetanus or antigen combinations. Concurrently, Innovaccines began work for the
development of an oral pertussis vaccine and sought ways to combine antigens
into a single oral vaccine.
The JV conducted numerous animal efficacy trials during 1999, 2000 and
2001, demonstrating the potential of antigen encapsulated in polymerized
liposomes to deliver tetanus antigen orally as well as intranasally. Animal
experiments in mice indicated
modest immunogenicity with tetanus antigen encapsulated in polymerized
liposomes, whereas best results were obtained with liposomes containing
lipophilic immunostimulatory adjuvants. A variety of liposomal formulations
were developed and evaluated using a clinically relevant lipophilic adjuvant
(monophosphoryl Lipid A, MPL) and a muramyldipeptide-based adjuvant
(Theramide(TM)). In separate animal experiments with adjuvant containing
formulations, 10% to 100% seroconversion was observed by oral vaccination. A
greater proportion of animals usually seroconverted by the nasal route. Minimum
criteria of animal efficacy were set such that an orally administered
formulation would not be advanced to clinical testing unless it had reproducibly
demonstrated at least 60% seroconversion with no more than 10-fold the amount of
antigen of the injected vaccine dose. As these criteria were not uniformly met,
Innovaccines developed more rigorous process controls and analytical procedures
for physically testing formulations. At this time, rigorous evaluation of
polymerized liposomes in comparison to unpolymerized liposome controls has been
completed. These results indicate that highly stable polymerized liposomes are
not effective for oral vaccination, with tetanus antigen. Consequently, less
stable liposome vehicles are thought to be potentially more relevant for
clinical development. As stability of encapsulated antigen in the
gastrointestinal tract is still considered important for oral vaccination,
Innovaccines is developing polymerized liposomes with low to moderate degrees of
stability and has switched its focus to lipophilic antigens (such as influenza
virus hemagglutinin).
Synthetic enterocyte of M-cell binding peptides have been identified.
Several of these peptides further characterized in rat ileal loop experiments
have been modified and covalently linked to the surface of vaccine candidate
liposomes. Evaluation of the targeting aspect of polymerized liposome vaccine
development is ongoing and will be reported in the next update.
In summary, none of the polymerized liposome tetanus vaccine formulations
has met minimum criteria for clinical development. Continuing work for
increasing absorption of large molecules into mucosal lymphoid tissue will
identify a suitable clinical candidate.
Toxicology
As polymerizable phospholipids and fatty acids have not yet been
classified as "GRAS" (generally regarded as safe), proper in vivo and in vitro
toxicology studies are necessary prior to clinical evaluation. All of the
candidate highly polymerized liposomes as well as the unpolymerized counterparts
have passed initial Xxxx testing, indicating little potential of these lipids
for mutagenicity or carcinogenicity. A full battery of toxicology tests will be
performed when an efficacious clinical candidate is identified.
Delivery of other protein or peptide therapeutics.
Human Growth Hormone
In December of 1999, Orasomal entered into R&D collaboration with Novo
Nordisk (NN) for the evaluation and development of orally administered human
growth hormone (hGH). Orasomal provided NN with preliminary preclinical data
demonstrating significant oral bioavailability of human growth hormone
encapsulated in polymerized liposomes. NN has since provided Orasomal with
sufficient quantities of purified growth hormone for both basic and scaled-up
formulations to replicate the original preliminary results and to move into oral
bioavailability testing in dogs and subsequently humans. Using the process
improvements and assay methodology developed for encapsulation and analysis of
tetanus toxoid antigen. Orasomal has applied similar techniques to growth
hormone and has achieved liposomal entrapment of biologically active growth
hormone in sufficient quantities for further animal evaluation. A rat model for
oral and regional gastrointestinal absorption has been employed in the latest
studies, in which formulations have been directly administered into the duodenum
via a surgically implanted cannula. Similar to tetanus vaccine studies, highly
stable polymerized liposomes are not effective to deliver growth hormone
intraduodenally or upon peroral administration. Unpolymerized or partially
polymerized liposomes, however, can deliver less than 1% hGH in the plasma
relative to injected controls. However, inconsistency and irreproducibility in
the absorption data were observed. Currently, the levels of hGH achieved in the
blood are not at the stage for clinical development.
Small Peptide and Lipophilic Drugs
The original hypothesis for the use of polymerized liposomes involved
high stability in the gastrointestinal tract and high level of uptake of the
intact liposomes through endocytotic mechanism through enterocytes or M cells in
the intestinal Xxxxx'x patches. In that case, size of the molecular payload was
secondary to the mechanism of particle endocytosis. Orasomal, based on available
data to date, believes that other mechanism(s) for liposome interaction with GI
mucosa are possible. Thus, molecular size may be an additional factor to
consider as it has been demonstrated in the literature for the intestinal
permeation of peptides and protein molecules using particulate systems.
Consequently, smaller therapeutic peptides may be more suitable candidates than
tetanus toxoid (M.W. - 150 kd) of hGH (M.W. 21 kd). Orasomal is pursuing that
hypothesis with low to moderately polymerized liposomes as well as tightly
cross-linked liposomes with LHRH (lutenizing hormone releasing hormone) as a
potential oral peptide to replace current implantable LHRH for endometriosis or
prostate cancer. In addition to LHRH, Orasomal is also pursuing oral insulin
(M.W. - 5000 kd).
Results of these evaluations will be provided during the next progress
report.
Patents
Orasomal has been responsible for prosecution of the original Xxxxxx polymerized
liposome application. There are currently three issued U.S. patents and one
C.I.P. pending for the technology licensed. One patent issued in 1998
(5,762,904). Since 1999, two of these patents have issued in the U.S.: 6,004,534
(12/21/99) and 6,060,082 (5/9/00). The latter two patents describe the use of
polymerized liposomes targeted with
specific lectins. Claims directed as use of any targeting ligand and any lectin
are being aggressively pursued in the C.I.P.
Expenses
On the attached page, the total accumulated expenses for the development of the
polymerized liposome technology are detailed.
Infrastructure
Orasomal has been operated as a subsidiary of Endorex Corporation since
inception.
Meetings and Publications
Since the last update, data describing oral and nasal vaccines and drug delivery
has been presented at several scientific meetings:
1. UK/Ireland CRS meeting 1/00.
2. ACS drug delivery meeting, San Francisco, 3/00.
Additional presentations in numerous corporate business development meetings and
investor meetings have also occurred. Recent publications from Orasomal or
Innovaccines describing this technology are as follows.
Xxxxx, M.A., Xxxxx, H., Xxxxx, L., Xxxx, X.X. et al. 2001. Targeting polymerized
liposome vaccine carriers to intestinal M cells. Vaccine, in press.
Lasic, D.D., X. Xxxxxxx, and X. X. Xxxx. 2000. Polymerized liposomes: from
biophysics to applications. Part 1. Chemistry Today. November/December, 2000.
Part 2, Feb-March 2001.
Xxxx, X. X. 2000. Polymerized liposomes as vehicles for mucosal delivery of
complex molecules. 2000. Pharma Tech. 2000. 172-176.
ATTACHMENT B
Orasomal Technologies, Inc.
Contributions by Endorex Corporation
as of October 18, 2001
License fees to MIT $ 38,328
Research funding to Xxxx Xxxxxxx 134,332
Other outside research 536,795
Consulting by Dr. Xxxxxx Xxxxxx and Xx. Xxxxx Xxxx 1,049,996
Other consultants and Scientific Advisory Board 205,893
R&D personnel 3,121,095
R&D laboratory 1,243,927
Patent expenditures 42,513
Senior management, finance and business development 1,546,647
Interest on loan from Endorex 1,158,530
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Total contributions $9,078,055
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