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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
For Annual and Transition Reports Pursuant to
Sections 13
or 15(d) of the Securities Exchange Act of 1934
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ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934 |
For the Fiscal Year Ended December 31, 2004
OR
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TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934 |
Commission File Number: 001-31918
HYBRIDON, INC.
(Exact name of Registrant as specified in its certificate of
incorporation)
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Delaware
(State or other jurisdiction
of incorporation or organization) |
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04-3072298
(I.R.S. Employer
Identification No.) |
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345 Vassar Street
Cambridge, Massachusetts
(Address of principal executive offices)
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02139
(Zip Code) |
(617) 679-5500
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the
Act: None
Securities registered pursuant to Section 12(g) of the
Act:
Common Stock, $.001 par value
(Including Associated Preferred Stock Purchase Rights)
(Title of Class)
Indicate by check mark whether the registrant (1) has filed
all reports required to be filed by Section 13 or 15(d) of
the Securities Exchange Act of 1934 during the preceding
12 months (or for such shorter period that the registrant
was required to file such reports), and (2) has been
subject to the filing requirements for the past
90 days. Yes þ No o
Indicate by check mark if disclosure of delinquent filers
pursuant to Item 405 of Regulation S-K is not
contained herein, and will not be contained, to the best of the
registrant’s knowledge, in definitive proxy or information
statements incorporated by reference in Part III of this
Form 10-K or any amendment to this
Form 10-K. o
Indicate by check mark whether the registrant is an accelerated
filer (as defined in Exchange Act
Rule 12b-2). Yes o No þ
The approximate aggregate market value of the voting stock held
by non-affiliates of the registrant was $60,166,000 based on the
last sale price of the registrant’s common stock on the
American Stock Exchange on June 30, 2004. As of
March 1, 2005, the registrant had 110,989,836 shares
of common stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
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Portions of the Registrant’s Proxy Statement with respect
to the Annual Meeting of Stockholders to be held on
June 15, 2005 |
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Items 10, 11, 12, 13 and 14 of Part III. |
HYBRIDON, INC.
FORM 10-K
INDEX
Hybridon®, IMOxine® and GEM® are our registered
trademarks.
Amplivaxtm,
CpRtm,
Cyclicontm,
IMOtm,
Immunomertm,
RpGtm,
YpGtm
and
YpRtm
are also our trademarks. Other trademarks appearing in this
annual report are the property of their respective owners.
i
PART I.
Overview
We are engaged in the discovery, development and
commercialization of novel therapeutics based on synthetic DNA
for the treatment of cancer, asthma/allergies and infectious
diseases. Our activities are primarily focused on the
development of our immunomodulatory oligonucleotide, or IMO,
technology. Our IMO compounds are synthetic DNA-based sequences
that are designed to mimic bacterial DNA and be recognized by a
specific protein receptor called Toll-like Receptor 9, or
TLR9, which triggers the activation and modulation of the immune
system. We also have been a pioneer in the development of
antisense technology, which uses synthetic DNA to block the
production of disease causing proteins at the cellular level. In
2003 and 2004, we devoted substantially all of our research and
development efforts to our IMO technology and products and
expect to continue to focus our research and development efforts
in 2005 and in future years on our IMO technology and products.
We plan to continue to seek to enter into collaborations with
third parties for the development and commercialization of
products based on our antisense technology.
Drug Development Strategy
In the near term, we are focusing our internal drug development
efforts on the lead IMO drug candidate in our pipeline, HYB2055.
We are developing HYB2055 for oncology applications under the
name IMOxine. In October 2004, we commenced patient recruitment
for an open label, multi-center phase 2 clinical trial of
IMOxine as a monotherapy in patients with metastatic or
recurrent clear cell renal carcinoma. We plan to recruit a
minimum of 46 patients into the first stage of the trial.
In addition to the phase 2 clinical trial of IMOxine, we
are conducting a phase 1 clinical trial of IMOxine in
patients with refractory solid tumor cancers, which was closed
to enrollment in November 2004. In November 2004, we announced
interim results of this phase 1 clinical trial of IMOxine,
which is being conducted at the Lombardi Comprehensive Cancer
Center at Georgetown University Medical Center in
Washington, D.C. We anticipate announcing further results
in the second quarter of 2005. In the interim results of the
phase 1 trial, IMOxine was found to be well tolerated with
no dose-limiting toxicity observed. Adverse effects recognized
through March 1, 2005 have been consistent with the
expected immune stimulation activity of IMOxine, consisting
primarily of mild to moderate injection site reactions, pain,
and “flu-like” symptoms. The interim results provided
evidence of dose response effects on immunology parameters in
patients with a variety of cancer types including patients with
renal cell carcinoma, melanoma, colorectal cancer, sarcoma,
breast cancer, non-small cell lung cancer and other cancers.
In addition to these trials, we may in the future conduct trials
in which we evaluate IMOxine for the treatment of other specific
types of cancer, as a monotherapy and/or in combination with
other anticancer agents, including chemotherapeutics,
antibodies, and vaccines/antigens.
Collaboration Strategy
In addition to developing drug candidates on our own, we are
seeking to establish alliances with other parties for the
development and commercialization of products based on our IMO
and antisense technologies.
We believe that pharmaceutical and biotechnology companies may
seek to use our IMO compounds as a monotherapy for the treatment
of specific diseases or in combination with, or as an adjuvant
to, their own chemotherapeutics, vaccines and monoclonal
antibodies. In particular, we are developing HYB2055 in a lower
dosage form, under the name Amplivax, for use as a vaccine
adjuvant. We licensed Amplivax to The Immune Response
Corporation for use in its development of a potential
therapeutic and prophylactic vaccine for HIV infection, and we
plan to seek additional licensees for Amplivax in the future. In
June 2004, The Immune Response Corporation initiated a
phase 1/2 clinical trial involving the use of Amplivax as
an adjuvant to REMUNE, an immune-based HIV therapeutic vaccine
being developed by The Immune Response Corporation.
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We also believe that our antisense technology may prove useful
to pharmaceutical and biotechnology companies that are seeking
to develop drug candidates that down-regulate gene targets
discovered by, or proprietary to, such companies. In addition to
collaborations based on gene targets whose proprietary rights
are controlled by third parties, we are seeking collaborators to
continue development of our most advanced antisense drug
candidate GEM231 and our other antisense drug candidates. GEM231
is a 2nd generation antisense compound for treating solid
tumor cancers that we developed to inhibit Protein Kinase A, or
PKA, a protein that has been shown to be present at increased
levels in the cells of many human cancers. We completed
enrollment of a phase 1/2 clinical trial of GEM231 as a
combination therapy with irinotecan, an anticancer drug marketed
in the United States under the name Camptosar®. We
presented interim data from this trial at the 2004 Annual
Meeting of the American Society of Clinical Oncology, or ASCO.
We have already entered into nine collaboration and licensing
agreements for our antisense technology including agreements
with Alnylam Pharmaceuticals, Inc. and VasGene Therapeutics Inc.
which were entered into during 2004. We are seeking to enter
into additional collaboration agreements for our antisense
technologies.
Our Product Pipeline
The table below summarizes the principal products that we or our
collaborators are developing and the therapeutic use and
development status of these products.
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| Product Description |
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Therapeutic Use |
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Development Status |
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IMO
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IMOxine1
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Cancer |
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phase 2 |
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Amplivax2
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HIV |
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phase 1/2 |
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IMOxine3
(used in combination)
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Cancer |
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preclinical candidate |
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HYB2093
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Asthma/allergy |
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preclinical candidate |
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HYB2125
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Hepatitis C |
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preclinical candidate |
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Antisense
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GEM2314
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Cancer |
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phase 1/2 |
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GEM640
(AEG35156)5
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Cancer |
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phase 1 |
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MBI11216
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Human papillomavirus |
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phase 1 |
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Veglin7
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Cancer |
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phase 1 |
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HYB676
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Ophthalmology |
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preclinical candidate |
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Being used as a monotherapy in patients with metastatic or
recurrent clear cell renal carcinoma. |
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Being used as an adjuvant in combination with REMUNE®, an
immune-based HIV therapeutic vaccine developed by The Immune
Response Corporation under a collaboration agreement with us. |
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Being used in combination with chemotherapy, selected monoclonal
antibodies and radiation. |
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We are seeking to enter into a collaboration for further
development of this product. |
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Being developed by Aegera Therapeutics, Inc. under a
collaboration agreement with us. |
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Migenix Inc. has the rights to develop MBI1121 under a
collaboration agreement with us. |
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Being developed by VasGene Therapeutics Inc. under a
collaboration agreement with us. |
In addition, we have developed several antisense drug candidates
for specific applications that are not currently in active
development programs but could be suitable candidates for
collaborations. These include:
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| Product Description |
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Therapeutic Use |
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Development Status |
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GEM92
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HIV |
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phase 1 |
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GEM240
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Cancer |
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preclinical candidate |
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Immunomodulatory Oligonucleotide (IMO) Technology
Overview
Our IMO technology has evolved from our research and clinical
experience with antisense oligonucleotides. We learned from this
research and clinical experience that some types of
oligonucleotides can act as potent stimulators of the immune
system. Our early insights and those of others showed that
oligonucleotides containing specific nucleotide segments, or
motifs, mimic in the human body the immune stimulating effects
of bacterial DNA. Nucleotides are the molecules that are linked
together to form DNA. Using our DNA chemistry, we have
designed and are developing a new, proprietary class of IMO
compounds. We believe these compounds, which we refer to as IMO
compounds, may offer a number of potential advantages over
earlier immune stimulatory oligonucleotides.
We are designing our IMO compounds to be used in the treatment
of conditions such as cancer, allergic asthma and other
allergies, and infectious diseases, either alone as a
monotherapy or in combination therapies with chemotherapeutics,
radiation, vaccines and antibodies.
Background
The human immune system protects the body against viruses,
bacteria and other infectious agents, referred to as pathogens.
It also acts to identify and eliminate abnormal cells, such as
cancer cells. The immune system works through various mechanisms
which recognize pathogens and abnormal cells. These mechanisms
initiate a series of interactions resulting in stimulation of
specific genes in response to the pathogens or abnormal cells.
The activities of the immune system are undertaken by its two
components: the innate immune system and the adaptive immune
system.
The role of the innate immune system is to provide a rapid,
non-specific response to a pathogenic invasion or to the
presence of a foreign substance in the body and to activate the
adaptive immune system. The innate immune system consists of
cells such as macrophages, dendritic cells and monocytes. When
the body is presented with a foreign pathogen, cells of the
innate immune system are activated, resulting in a cascade of
signaling events that cause the production of proteins to fight
the infection. Unlike the antibodies and proteins produced by
the adaptive immune system described below, the proteins
produced by the innate immune system are not pathogen-specific,
but rather are active against a broad spectrum of pathogens.
Moreover, once the infection is resolved, the innate immune
system will not remember the pathogen.
In contrast to the innate immune system, the adaptive immune
system provides a pathogen-specific response to a pathogenic
invasion. The adaptive immune system does this by recognition of
specific cell surface proteins, called antigens, which signal
the presence of a pathogen. This process is initiated through
signals produced by the innate immune system. Upon recognition
of a foreign antigen, the adaptive immune system produces
antibodies and antigen-specific toxic immune cells that
specifically detect and destroy infected cells. This response is
referred to as an antigen-specific immune response. An
antigen-specific immune response normally takes several weeks to
develop the first time. However, once activated by a specific
pathogen, the adaptive immune system “remembers” the
antigens of the pathogen. In this manner, if the pathogen again
invades the body, the presence of the “remembered”
antigens will allow the adaptive immune system to respond once
more, this time in a matter of days. Scientists generally
believe that the adaptive immune system also may be able to
eliminate abnormal cells, such as cancer cells.
The human immune reaction is initially commenced by activation
of the innate immune system. One way this occurs is through
recognition by the immune system of a pathogen-associated
molecular pattern, referred to as a PAMP. These patterns include
components of DNA that are present with great frequency in
pathogens and with low frequency, or not at all, in humans. The
presence of a PAMP acts as a signal to the immune system of the
presence of a foreign pathogen and starts an immune response.
In the case of bacteria, one common PAMP is a combination of DNA
known as a CpG dinucleotide or CpG DNA. A CpG dinucleotide, or
motif, consists of a cytosine (C) molecule and guanine
(G) molecule linked by a phosphate bond (p). Most bacteria
contain this CpG motif at the expected frequency of one in
sixteen base pairs in their genome. Vertebrates, including
humans, display many fewer CpG dinucleotides, and
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usually the cytosine (C) molecule of the CpG motif is
methylated, unlike bacterial CpG dinucleotides where the
cytosine (C) molecule is unmethylated. Methylation is the
substitution of a methyl group, a molecule containing one carbon
atom and three hydrogen atoms, for a hydrogen atom. In this way,
self DNA, which is methylated, is not mistaken for pathogen DNA.
CpG DNA has been shown to be recognized by a specific protein
receptor called Toll-like Receptor 9, or TLR9. TLR9 is
located inside some types of immune cells. Scientists generally
believe that once TLR9 recognizes bacterial DNA, such as CpG
DNA, it triggers an immune response through a cascade of cell
signals that ultimately leads to the release of immune system
molecules both from the innate and eventually the adaptive
immune systems. These molecules attack the infection. Additional
receptors other than TLR9 may also contribute to or modify the
recognition of certain CpG DNA, emphasizing the structural
importance of CpG DNA in TLR-specific signaling.
Our IMO compounds are intended to mimic bacterial DNA. We
believe the sequences of these compounds are recognized as
bacterial DNA by TLR9 and possibly other receptors. As a result,
we believe that our IMO compounds can trigger an innate immune
response similar to the innate immune response triggered by
bacterial DNA. Results from our preclinical studies and our
initial clinical trials of our IMO compounds suggest this
response leads to signaling events that include production of
cytokines. Cytokines are a specific type of immune system
molecule that are known to have broad spectrum therapeutic
properties against infectious disease as well as against cancer.
These signals from the innate immune system also may trigger
responses of the adaptive immune system.
Because recognition of IMO compounds by TLR9 or other receptors
may lead to both innate and adaptive immune responses, we
believe IMO compounds may have the potential to be useful in
treatment of a wide variety of diseases either as a monotherapy
or in combination with other agents such as chemotherapeutics,
radiation, vaccines, antigens and monoclonal antibodies. We and
independent third parties who are investigating CpG DNA drug
candidates that work in a manner similar to our IMO compounds
are currently exploring the use of these drug candidates in
clinical trials for cancer, asthma, allergies and infectious
diseases.
Therapeutic Potential of IMO Compounds
Because IMO compounds can generate a broad range of immune
responses, we believe they may provide therapeutic benefits in a
number of areas:
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Cancer. Cancer cells are recognized by the body as
abnormal cells and trigger an immune response. However, the
body’s immune response to cancer cells is notoriously weak.
The benefits of immune stimulation by bacterial DNA in cancer
patients have been long recognized. IMO compounds have been
shown to activate dendritic cells and B cells and induce Th1
cytokine secretion in human cell-based assays. The secreted
cytokines are known to stimulate natural killer cells to destroy
cells within a tumor mass. In pre-clinical studies in mouse
models, our IMO compounds have also been shown to enhance the
activity of selected chemotherapeutic agents, selected
anticancer antibodies and radiation. |
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Allergic Asthma and Other Allergies. Based on preclinical
studies of our IMO compounds in mouse models, we believe that
IMO compounds have potential for use in the treatment of
allergic asthma, other allergies and other diseases that result
from an overreaction of the immune system by suppressing
specific allergen induced allergic responses. In these studies
the type of cytokines produced as a result of the activation of
immune cells by IMO compounds suppressed asthmatic and allergic
immune conditions while simultaneously promoting an immune
response that further alleviated asthmatic and allergic
conditions. |
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Infectious Diseases. According to published reports,
various CpG DNA sequences have been shown in studies in mice and
other animals to activate an immune defense against pathogens
that is of a general nature and not directed at any specific
microorganism. As a result, we believe that our IMO compounds
have the potential to be used prophylactically to ward off the
danger of infection or to boost the immune response to an
early-stage or ongoing infection. Some of our IMO compounds have
been shown in ongoing preclinical studies to induce Th1-type
cytokines, IFN-α in non-human primate |
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studies for example. These cytokines are useful as
anti-infectious agents against bacteria, viruses, and parasites.
We have a portfolio of various IMO structures, including
compounds that induce high levels of IFN-α, which may be
suitable for treating Hepatitis C and other viral
infections. |
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Combinations with Vaccines. In preclinical studies in
mice, the immune response triggered by IMO compounds has
been shown to increase the effectiveness of vaccines and
peptides. As a result, we believe that IMO compounds have
the potential to be used in combination with, or as an adjuvant
to, vaccines. The Immune Response Corporation is evaluating our
Amplivax IMO compound for use as an adjuvant in combination
with REMUNE in a phase 1/ 2 clinical trial. |
IMO Chemistry
Based on our expertise in synthetic oligonucleotide chemistry
compiled over the past fifteen years, we have developed a
portfolio of IMO compounds containing different proprietary
synthetic motifs and different site-specific sequences. In our
preclinical studies of several IMO compounds and initial
clinical trials of our lead IMO compound, our
IMO compounds have triggered an immune response that has
resulted in the expression of many cytokines. This immune
response and the resulting expression of cytokines have varied
depending on the sequence and structure of the IMO compound. We
believe that by varying the synthetic motifs, site-specific
sequences and secondary structures in the IMO compounds, we can
design IMO compounds that optimize immunostimulatory activity
and induce different profiles of immune response. As a result,
we believe we may create IMO compounds that are optimized
for the treatment of different diseases.
HYB2055 Drug Discovery and Development
IMOxine
We are focusing our internal drug development efforts on the
lead drug candidate in our pipeline, HYB2055, for oncology
applications under the name IMOxine. We selected HYB2055 for
clinical development because of the potency it demonstrated as
an immune modulator in preclinical models, both in vitro
and in vivo. We filed an Investigational New Drug
Application, or IND, for HYB2055 with the FDA that became
effective March 6, 2003.
In March 2004, we completed a phase 1 clinical trial of
HYB2055 in 28 healthy volunteers over a broad range of
dosing levels. In this trial, HYB2055 was well tolerated by the
volunteers, who did not experience any significant
treatment-related adverse effects. In addition, HYB2055
demonstrated biological activity in the volunteers, according to
the several parameters monitored in the study.
In May 2003, we commenced a phase 1 clinical trial of
IMOxine in patients with refractory solid tumor cancers at the
Lombardi Comprehensive Cancer Center at Georgetown University
Medical Center in Washington, D.C. We announced enrollment
completion and interim results from the phase 1 oncology
trial in November 2004. We enrolled 23 patients in this
trial and one patient continues to receive IMOxine treatment as
of March 1, 2005 (for over one year). Interim results from
the trial included that IMOxine was found to be well tolerated
with no significant dose-limiting toxicity observed. The adverse
effects patients experienced as of the November 2004
announcement were consistent with the expected immune
stimulation activity of IMOxine, and primarily have been mild to
moderate injection site reactions, pain and “flu-like”
symptoms including rigors/chills, fever, nausea, myalgia,
headache, malaise and fatigue. Observations that were considered
serious adverse events and possibly related to IMOxine treatment
have been transient dyspnea with hypoxia (1 patient),
rigors/chills 1 hour post dose (1 patient), abdominal
pain with nausea/vomiting (1 patient) and anemia requiring
transfusion (2 patients). The one patient continuing to
receive IMOxine therapy has had no additional adverse effects
since the November 2004 announcement. The interim results of
this phase 1 trial provided evidence of dose response
effects on immunology parameters in patients with a variety of
cancer types, including renal cell carcinoma, melanoma,
colorectal cancer, sarcoma, breast cancer, non-small cell lung
cancer and other cancers.
In February 2005, Hybridon agreed to support a single-patient
investigator-sponsored IND involving the weekly administration
of IMOxine at a dosage of 0.64 mg/ kg per week. The
investigator is Michael
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Seiden, M.D., Ph.D., of Massachusetts General
Hospital. The single patient has chemotherapy resistant
epithelial ovarian carcinoma.
We are currently conducting a phase 2 clinical trial of
IMOxine in patients with metastatic or recurrent clear cell
renal carcinoma. The trial, for which we began patient
recruitment in October 2004, is a two-stage, multi-center, open
label study of IMOxine as a monotherapy. The primary objective
of the study is to determine tumor response by Response
Evaluation Criteria in Solid Tumors, or RECIST. Secondary study
objectives are safety, duration of response, time to
progression, survival one year after the last dose and the
treatment effect on quality of life. In the trial, one of two
dose levels of 0.16 or 0.64 mg/ kg is administered by
weekly subcutaneous injection. Treatment duration is defined as
24 weeks based on safety and the absence of disease
progression. We expect that patients can continue to receive
IMOxine treatment beyond 24 weeks based on investigator
recommendations and independent medical monitor concurrence. We
plan to recruit a minimum of 46 patients in the first stage
of the trial and anticipate preliminary results related to the
primary objective within the first half of 2006. We expect the
second stage of the trial to be a continuation of the same trial
design if warranted by the first stage interim results.
In addition to cancer applications, we are also developing
HYB2055 for use as a vaccine adjuvant. We are developing HYB2055
in a lower dosage form under the name Amplivax for these
applications. We licensed Amplivax to The Immune Response
Corporation for use in its development of a potential
therapeutic and prophylactic vaccine for HIV infection, and
we plan to seek additional licensees for Amplivax in the future.
In June 2004, The Immune Response Corporation initiated a
phase 1/ 2 clinical trial involving the use of Amplivax as
an adjuvant to REMUNE, an immune-based HIV therapeutic
vaccine being developed by The Immune Response Corporation.
We believe that HYB2055, or similar compounds based on our
IMO technology, may also be used as a monotherapy for
treatment of infectious diseases, allergic asthma and other
allergies. We may explore the potential of these uses either on
our own, or with collaborators through submission of additional
INDs.
Antisense Technology
Overview
Most drugs are chemicals that stimulate or suppress the function
of a particular molecule, usually a protein, which causes a
disease. The drug acts by binding to the target molecule and
interrupting the disease-causing activity of the target
molecule. Frequently, however, sites on other non-target
molecules present in the body resemble the target-binding site
of a disease-causing molecule and, as a result, the conventional
drug binds to some degree to those non-target molecules. Most
drug side effects arise due to this off-target activity.
In contrast, antisense drug candidates interact with the target
molecule with extremely high specificity. Antisense drug
candidates are designed to bind to a unique messenger RNA (mRNA)
target and thereby block production of the specific protein
encoded by the target mRNA. We believe that drugs based on
antisense technology may be more effective and cause fewer side
effects than conventional drugs because antisense drugs are
designed to intervene in a highly specific fashion in the
production of proteins, rather than after the proteins are made.
Background
A normal cell produces a particular set of normal proteins in
the right amount for the body to function properly. A diseased
cell produces inappropriate proteins or the wrong amount of
normal proteins. A cell produces inappropriate types or amounts
of proteins when its DNA expression changes, either through
mutation as in many types of cancer cells or through an
imbalance of normal bodily function. In some
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instances, inappropriate proteins act directly to cause or
support a disease. In other instances, inappropriate proteins
interfere with proteins that prevent or combat disease.
Cells make proteins in a two-stage process. All proteins are
based on the DNA which comprises the cellular genome. DNA is a
string of individual building blocks chemically known as
nucleotides. The specific sequence in which the nucleotides are
arranged is the code that embodies genetic information into the
DNA. First, the cell uses its genetic DNA code as a pattern
to create a molecule of messenger RNA or mRNA consisting of a
string of nucleotides in a sequence that is the exact mirror
image of, or complementary to, the sequence of the coding strand
of nucleotides in the DNA. This mRNA strand is called the
“sense” sequence. In the next step, the cell
translates the information contained in the “sense”
sequence into a specific protein.
Therapeutic Potential of Antisense Compounds
A synthetic DNA molecule with a sequence exactly complementary
to a portion of a specific mRNA can bind to and inhibit the
function of that mRNA. This exact complement of the sense mRNA
is referred to as an antisense oligonucleotide. By inhibiting
binding to a specific mRNA target, the antisense oligonucleotide
blocks synthesis of the protein.
We believe that the pharmaceutical industry is increasingly rich
in potential gene-based drug targets. We further believe that
the increase in the number of potential targets provides us with
increasing opportunities to employ our antisense technology.
Once a gene coding for a disease-associated protein is
identified, it should be possible to design a synthetic DNA with
an antisense mechanism designed to stop production of that
protein. Moreover, in contrast with small molecule drug
discovery which may take many years, we can design an antisense
drug candidate for a gene target in about 90 days after
that gene target has been identified.
Hybridon Antisense Technology
We and other companies recognized early in the exploration of
antisense technology that natural DNA-based oligonucleotides are
not suitable as drug candidates because they are rapidly
degraded in the blood and other tissues before they can reach
their intended target within cells. Early modifications made by
us and other companies to increase the biological stability of
oligonucleotides lead to a chemical class of oligonucleotides
which we refer to as 1st generation antisense compounds. To
date, the FDA has approved only one 1st generation
antisense compound, which one of our competitors developed and
which is currently marketed by Novartis Ophthalmics to treat a
viral infection through local delivery. Several
1st generation antisense drug candidates of third parties
have failed to show activity in late stage clinical trials.
We have focused our efforts on the design and creation of more
advanced synthetic DNA chemistries which we refer to as
2nd generation antisense compounds. We believe that
2nd generation antisense compounds may show more favorable
pharmaceutical characteristics and significantly improved
therapeutic utility as compared to 1st generation antisense
compounds. We believe that these 2nd generation antisense
compounds may exhibit the following desirable characteristics in
comparison with 1st generation compounds: (1) fewer
side effects; (2) greater stability in the body, enabling
patients to take doses less frequently; (3) greater
potency, permitting patients to take lower doses; and
(4) greater potential for multiple routes of
administration, including by injection, orally or topically.
The following companies have licensed Hybridon’s antisense
technology: Aegera Therapeutics, Inc., Alnylam Pharmaceuticals,
Inc., Avecia Biotechnology, Epigenesis Pharmaceuticals, Inc.,
Integrated DNA Technologies, Inc., Isis Pharmaceuticals, Inc.,
Methylgene Inc., Migenix Inc. and VasGene Therapeutics Inc.
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Antisense Drug Development and Discovery |
GEM231 for the Treatment of Cancer. GEM231 is designed to
inhibit protein kinase A, or PKA. PKA is a protein that
plays a key role in the control of the growth and
differentiation of mammalian cells. Levels of PKA have been
shown to be increased in the cells of many human cancers. GEM231
has been shown to have preclinical anti-tumor activity in models
of various types of cancer, alone and in combination with various
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agents. In August 2004, we completed enrollment of a
phase 1/ 2 clinical trial of GEM231 at Vanderbilt
University Medical Center as a combination therapy with
irinotecan, an anticancer drug marketed in the United States
under the name Camptosar®. In March 2004, we presented
interim data from this trial showing that the combination of
irinotecan at 125 mg/
m2
with GEM231 at 40 mg/
m2 per
day was well tolerated in patients in the trial. Higher dosages
of irinotecan and/or GEM231 were associated with dose-limiting
toxicities such as fatigue, nausea, diarrhea, anorexia, weight
loss and death attributable to pulmonary embolism. Preliminary
evidence was seen of GEM231 effects on PKA activity in the blood
and on irinotecan pharmacokinetics. We expect to collect and
analyze the final data from the trial by the end of 2005. Even
if the final pharmacokinetic data and other findings from this
phase 1/ 2 trial are favorable, we do not plan to continue
further development of GEM231 without a collaborator.
One patient who was withdrawn from the Hybridon sponsored trial
due to prolonged treatment interruption was enrolled onto a
single-patient physician-sponsored IND held by Mace
Rothenberg, M.D., of Vanderbilt Medical Center. The single
patient had breast cancer and received 125 mg/
m2
of irinotecan plus 40 mg/
m2 per
day of GEM231.
GEM640/ AEG35156 is an antisense compound being developed by
Aegera Therapeutics, Inc. under a collaboration with us. GEM640
is targeted to the XIAP protein and is intended for the
treatment of cancer. XIAP is an inhibitor of apoptosis, which is
the process by which disrupted cells are dismantled without
causing inflammation or other response. Cancer cells often fail
to undergo apoptosis despite damage caused by chemotherapy or
radiotherapy. Aegera began a phase 1 trial of GEM640/
AEG35156 in 2004.
Veglintm
is an antisense drug candidate being developed by VasGene
Therapeutics, Inc. and targeted against Vascular Endothelial
Growth Factor (VEGF). VEGF contributes to the growth of new
blood vessels, which is critical to disease processes including
cancer and macular degeneration. In June 2004, VasGene announced
the presentation of phase 1 data. The primary objective of
this study was to determine the Maximum Tolerated Dose (MTD) and
toxicity profile of Veglin among relapsed and refractory
patients with a variety of tumor types. Patients in the trial
received Veglin intravenously by two-hour infusion for five days
followed by a seven-day rest period, for a maximum treatment
duration of four months. Results demonstrated that Veglin was
well tolerated by patients with a wide variety of cancers.
VasGene anticipates initiating multi-center phase 2
clinical trials during 2005 for patients with renal cell
carcinoma and/or other specific malignancies.
GEM92 is an antisense compound that is targeted to a specific
region of the genome of the human immunodeficiency virus HIV-1
known as the gag region. In 1997, we conducted a
phase 1 study that showed GEM92 was well tolerated by the
participating subjects. We are not currently pursuing
development of GEM92.
We have two principal antisense compounds that we are developing
in the preclinical testing phase:
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HYB676 is a 2nd generation antisense agent targeted to VEGF
as a potential drug candidate for age-related macular
degeneration. |
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GEM240 is targeted to inhibit the protein mdm2 which is
increased in many human cancers. |
Research and Development
For the years ended December 31, 2004, 2003 and 2002, we
spent approximately $10.3 million, $10.8 million and
$7.9 million, respectively, on research and development
activities. Our collaborators sponsored only a nominal portion
of these research and development activities in 2004, 2003 and
2002.
8
Patents, Proprietary Rights and Licenses
Patents and Proprietary
Rights
Our success depends in part on our ability to obtain and
maintain proprietary protection for our product candidates,
technology and know-how, to operate without infringing the
proprietary rights of others and to prevent others from
infringing our proprietary rights. Our policy is to seek to
protect our proprietary position by, among other methods, filing
U.S. and foreign patent applications related to our proprietary
technology, inventions and improvements that are important to
the development of our business. We also rely on trade secrets,
know-how, continuing technological innovation and in-licensing
opportunities to develop and maintain our proprietary position.
As of December 31, 2004, we owned 29 U.S. patents and
U.S. patent applications and over 80 corresponding
world wide patents and patent applications relating to our IMO
technology. As of December 31, 2004, we owned or
exclusively licensed over 532 world wide patents and patent
applications relating to our antisense technology of which 137
are U.S. patents and U.S. patent applications. The
issued patents held or exclusively licensed by us include
composition of matter patents on our own advanced DNA
chemistries covering the use of these chemistries with various
genes or sequences, patents covering therapeutic targets,
patents covering immune modulation and patents covering oral and
other routes of administering our synthetic DNA. These issued
patents expire at various dates ranging from 2006 to 2022.
The composition of matter patents covering GEM231 expire at
various dates ranging from 2010 to 2022. We have applied for
composition of matter patents covering HYB2055.
The patent positions of companies like ours are generally
uncertain and involve complex legal and factual questions. Our
ability to maintain and solidify our proprietary position for
our technology will depend on our success in obtaining effective
claims and enforcing those claims once granted. We do not know
whether any of our patent applications or those patent
applications which we license will result in the issuance of any
patents. Our issued patents and those that may issue in the
future, or those licensed to us, may be challenged, invalidated
or circumvented, and the rights granted thereunder may not
provide us proprietary protection or competitive advantages
against competitors with similar technology. Furthermore, our
competitors may independently develop similar technologies or
duplicate any technology developed by us. Because of the
extensive time required for development, testing and regulatory
review of a potential product, it is possible that, before any
of our products can be commercialized, any related patent may
expire or remain in force for only a short period following
commercialization, thus reducing any advantage of the patent,
which could adversely affect our ability to protect future drug
development and, consequently, our operating results and
financial position.
Because patent applications in the United States and many
foreign jurisdictions are typically not published until eighteen
months after filing, or in some cases not at all, and because
publications of discoveries in the scientific literature often
lag behind actual discoveries, we cannot be certain that we were
the first to make the inventions claimed in each of our issued
patents or pending patent applications, or that we were the
first to file for protection of the inventions set forth in
these patent applications.
Litigation may be necessary to defend against or assert claims
of infringement, to enforce patents issued to us, to protect
trade secrets or know-how owned by us, or to determine the scope
and validity of the proprietary rights of others. In addition,
the U.S. Patent and Trademark Office may declare
interference proceedings to determine the priority of inventions
with respect to our patent applications or reexamination or
reissue proceedings to determine if the scope of a patent should
be narrowed. Litigation or any of these other proceedings could
result in substantial costs to and diversion of effort by us,
and could have a material adverse effect on our business,
financial condition and results of operations. These efforts by
us may not be successful.
Trade Secrets
We may rely, in some circumstances, on trade secrets to protect
our technology. However, trade secrets are difficult to protect.
We seek to protect our proprietary technology and processes, in
part, by confidentiality agreements with our employees,
consultants, scientific advisors and other contractors. There
can be no
9
assurance that these agreements will not be breached, that we
will have adequate remedies for any breach, or that our trade
secrets will not otherwise become known or be independently
discovered by competitors. To the extent that our employees,
consultants or contractors use intellectual property owned by
others in their work for us, disputes may also arise as to the
rights in related or resulting know-how and inventions.
Licenses
We are a party to a number of royalty-bearing license agreements
under which we have acquired rights to patents, patent
applications and technology of third parties. Our principal
license agreement is with University of Massachusetts Medical
Center. Under the terms of our license agreement with the
University of Massachusetts Medical Center, we are the
worldwide, exclusive licensee under a number of U.S. issued
patents and various patent applications owned by UMass Medical
Center relating to antisense oligonucleotides and their
production and use. Many of these patents and patent
applications have corresponding applications on file or
corresponding patents in other major industrial countries. The
patents licensed to us by the University of Massachusetts
Medical Center expire at dates ranging from 2006 to 2019. This
license expires upon the expiration of the last to expire of the
patents covered by the license.
Other license agreements under which we are the licensee include:
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an exclusive license agreement with Louisiana State University
covering patents and patent applications jointly owned by us and
Louisiana State University relating to mdm2, |
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a non-exclusive license agreement with Genzyme Corporation
covering patents and patent applications relating to mdm2, |
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a non-exclusive license agreement with Integrated DNA
Technologies, Inc., covering patents and patent applications
that broadly claim chemical modifications to synthetic DNA, |
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an exclusive license agreement with Dr. Yoon S. Cho-Chung
covering patents and patent applications relating to Protein
Kinase A, |
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an exclusive license agreement with Children’s Hospital
Medical Center covering patents and patent applications relating
to VEGF and |
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a non-exclusive license agreement with VasGene Therapeutics,
Inc. covering patents and patent applications relating to the
use of VEGF for ophthalmic applications. |
Under these licenses we are obligated to pay royalties on net
sales by us of products or processes covered by a valid claim of
a patent or patent application licensed to us. We also are
required in some cases to pay a specified percentage of any
sublicense income that we may receive. These licenses impose
various commercialization, sublicensing, insurance and other
obligations on us. Our failure to comply with these requirements
could result in termination of the licenses. Each of these
licenses terminates upon the expiration of the last to expire of
the patents covered by the license.
Corporate Alliances
An important part of our business strategy is to enter into
research and development collaborations, licensing agreements
and other strategic alliances, primarily with biotechnology and
pharmaceutical corporations, to develop and commercialize drugs
based on our technologies.
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Isis Pharmaceuticals, Inc. |
We are a party to a collaboration and license agreement with
Isis Pharmaceuticals, Inc. Under the agreement, we granted Isis
a license, with the right to sublicense, to our antisense
chemistry and delivery patents and patent applications. We
retained the right to use these patents and patent applications
in our own drug discovery and development efforts and in
collaborations with third parties. In consideration of the
license, in 2001 Isis paid us $15.0 million in cash and
issued to us 857,143 shares of its common stock having an
aggregate fair market value on the date of issuance of
$17.3 million. Under the agreement, Isis is also required
10
to pay us a portion of specified sublicense income it receives
from some types of sublicenses of our patents and patent
applications. In 2003 and 2004, Isis made such payments to us in
connection with sublicenses of our patents and patent
applications.
In addition under the agreement, we licensed from Isis specified
antisense patents and patent applications, principally
Isis’ suite of RNase H patents and patent applications. We
have the right under the agreement to use these patents and
patent applications in our drug discovery and development
efforts and in some types of collaborations with third parties.
In consideration of this license, in 2002 we paid Isis
approximately $716,000 in cash and issued to Isis
1,005,499 shares of our common stock having an aggregate
fair market value on the date of issuance of approximately
$1.2 million. We also agreed to pay Isis a nominal annual
maintenance fee and a modest royalty on sales of products
covered by specified patents and patent applications sublicensed
to us by Isis. The licenses granted under the Isis agreement
terminate upon the last to expire of the patents and patent
applications licensed under the agreement. We may terminate at
any time the sublicense by Isis to us of the patents and patent
applications for which we have maintenance fee and royalty
obligations to Isis.
We are a party to nine other collaboration and license
arrangements involving the use of our IMO or antisense
technologies and specified indications. Some of these include:
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VasGene Therapeutics, Inc. On October 29, 2004, we
entered into reciprocal Collaboration and License Agreements
with VasGene Therapeutics, Inc. pursuant to which both parties
agreed to collaborate on the research and development of VEGF
antisense products. We intend to pursue the treatment of
opthalmologic and other non-cancer diseases that are susceptible
to treatment based on localized administration under one
agreement, and VasGene intends to pursue the treatment of cancer
and other non-ophthalmologic diseases that are susceptible to
treatment through systemic administration under the other
agreement.
We are entitled to receive milestone payments, royalties, and
sublicensing payments. Additionally, we would be entitled to
reimbursement of research services we perform in accordance with
the terms of the agreement at the request of VasGene. We may
have to pay VasGene royalties and sublicensing payments.
Likewise, VasGene would be entitled to reimbursement of research
services that it performed under the agreement at our request.
The milestones, if fully achieved, would result in payments to
us totalling $8.0 million for each non-cancer VEGF
antisense product developed by VasGene. Milestone payments would
be triggered by the achievement of specific events in the
development and commercial launch process. |
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Alnylam Pharmaceuticals, Inc. On August 2, 2004, we
entered into a Collaboration and License Agreement with Alnylam
Pharmaceuticals, Inc. pursuant to which we granted to Alnylam an
exclusive license to a series of patents and patent applications
relating to the therapeutic use of oligonucleotides that inhibit
the production of the protein VEGF. Under the license,
Alnylam’s rights are limited to targeting VEGF for ocular
indications with RNAi molecules. We are entitled to receive an
up-front payment, annual license fees, milestone payments,
royalties and sublicensing payments from Alnylam under the terms
of the agreement. The upfront payment, license fees and
milestone payments payable to us under the agreement could total
approximately $4.4 million, if all the milestones are
achieved. Milestone payments are triggered by the achievement of
specific events in the development process. |
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Aegera Therapeutics Inc. We are a party to an agreement
with Aegera Therapeutics, Inc. that relates to the development
of an antisense drug targeted to the XIAP gene, a gene which has
been implicated in the resistance of cancer cells to
chemotherapy. In July 2003, Aegera and we announced that we had
selected AEG35156/GEM640, an antisense oligonucleotide, targeted
to the XIAP gene, as the development candidate. Aegera has
advised us in 2003 that it has completed preclinical toxicology
studies of AEG35156/GEM640 and in 2004, that it initiated a
phase 1 clinical trial in the first quarter of 2004. Under
the terms of the license we may receive up to approximately
$7.7 million in up-front |
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and milestone payments upon the achievement of specified
development milestones. We are also entitled to receive a
royalty on net sales of any drugs that are approved for sale. |
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The Immune Response Corporation. We are a party to an
agreement with Immune Response that relates to the development
of Amplivax as an adjuvant for use in combination with Immune
Response’s REMUNE® vaccine candidate for the
prevention and treatment of HIV-1. Under the terms of the
agreement, we granted Immune Response, during an exclusivity
period, a worldwide license to Amplivax as an HIV vaccine
adjuvant for the prevention and treatment of HIV. In order to
maintain the exclusivity of the license, Immune Response must
make payments to us at specified times under the agreement. We
are also entitled to receive a royalty on net sales of the
REMUNE vaccine combined with Amplivax if it is approved for sale. |
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Migenix Inc. (formerly Micrologix Biotechnology, Inc.) We
are a party to an agreement with Migenix that relates to the
development of an antisense drug for the treatment of human
papillomavirus. Origenix, a former subsidiary of ours, and the
entity from which Migenix acquired the rights to the
development, previously conducted a phase 1 clinical trial
of this drug candidate. Under the terms of the agreement we may
receive, in cash or equity, up to approximately
$5.8 million in up-front and milestone payments upon the
achievement of specified development milestones. We are also
entitled to receive a royalty on net sales of the drug if it is
approved for sale. |
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Epigenesis Pharmaceuticals, Inc. We are a party to an
agreement with Epigenesis that relates to the development of up
to five antisense drugs for the treatment of respiratory
disease. Under the agreement, we received an upfront payment and
are entitled to receive a royalty on net sales of the drug if it
is approved for sale. |
Under these arrangements, we typically license to our
collaborators our chemistries and delivery patents and patent
applications on a non-exclusive basis, and any patents and
patent applications that we have that are directed at the genes
that are the subject of the arrangement on an exclusive basis.
In addition, although our collaborators are responsible for the
development and commercialization of the product, we typically
provide specified research, development and compound
optimization services to our collaborators. In consideration for
the license and these services, we typically are entitled to
receive license fees and are entitled to receive research
payments, payments upon achievement of development milestones
and royalties on product sales and sublicensing, if earned. The
licenses granted under these agreements typically terminate upon
the later of the last to expire of the patents licensed under
the agreements or a specified number of years after the first
commercial sale of products covered by the agreements. These
agreements may be terminated by either party upon a material
breach. Our collaborators may terminate these agreements at any
time upon written notice.
Academic and Research Collaborations
We have entered into a number of collaborative research
relationships with independent researchers, leading academic and
research institutions and U.S. government agencies. These
research relationships allow us to augment our internal research
capabilities and obtain access to specialized knowledge and
expertise.
In general, our collaborative research agreements require us to
pay various amounts to support the research. We usually provide
the synthetic DNA for the collaboration, which the collaborator
then tests. If in the course of conducting research under its
agreement with us a collaborator, solely or jointly with us,
creates any invention, we generally have an option to negotiate
an exclusive, worldwide, royalty-bearing license to the
invention. Inventions developed solely by our scientists in
connection with a collaborative relationship generally are owned
exclusively by us. Most of these collaborative agreements are
nonexclusive and can be cancelled with limited notice.
Government Regulation
The testing, manufacturing, labeling, advertising, promotion,
distribution, import, export, and marketing, among other things,
of drugs are extensively regulated by governmental authorities
in the U.S. and other countries. In the U.S., the FDA regulates
pharmaceutical products under the Federal Food, Drug, and
12
Cosmetic Act, or FDCA, and other laws. Both before and after
approval for marketing is obtained, violations of regulatory
requirements may result in various adverse consequences,
including the FDA’s delay in approving or refusal to
approve a drug, withdrawal of approval, suspension or withdrawal
of an approved product from the market, operating restrictions,
warning letters, product recalls, product seizures, injunctions,
fines, and the imposition of civil or criminal penalties.
The steps required before a product may be approved for
marketing in the U.S. generally include:
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preclinical laboratory tests and animal tests under the
FDA’s good laboratory practices regulations; |
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the submission to the FDA of an investigational new drug
application, or IND, for human clinical testing, which must
become effective before human clinical trials may begin; |
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adequate and well-controlled human clinical trials to establish
the safety and efficacy of the product for each indication; |
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satisfactory completion of an FDA inspection of the
manufacturing facility or facilities at which the product is
made to assess compliance with the FDA’s current good
manufacturing practices regulations, or cGMP; and |
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the submission to the FDA of a new drug application, or NDA. |
Preclinical tests include laboratory evaluation of the product,
as well as animal studies to assess the potential safety and
efficacy of a drug. The results of the preclinical tests,
together with manufacturing information and analytical data, are
submitted to the FDA as part of an IND, which must become
effective before human clinical trials may be commenced. The IND
will automatically become effective 30 days after its
receipt by the FDA, unlessthe FDA before that time raises
concerns or questions about the conduct of the trials as
outlined in the IND. In such a case, the IND sponsor and the FDA
must resolve any outstanding concerns before clinical trials can
proceed. If these issues are unresolved, the FDA may not allow
the clinical trials to commence. There is no guarantee that
submission of an IND will result in the FDA allowing clinical
trials to begin.
Clinical trials typically are conducted in three sequential
phases, but the phases may overlap or be combined. Clinical
trials are conducted under protocols detailing the objectives of
the trials, the parameters to be used in monitory safety and the
effectiveness criteria to be evaluated. Each protocol must be
submitted to the FDA as part of the IND prior to beginning the
trial. Each trial must be reviewed and approved by an
independent Institutional Research Board before it can begin.
Subjects must provide informed consent for all trials.
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In phase 1, the initial introduction of the drug into human
subjects, the drug is usually tested for safety or adverse
effects, dosage tolerance, and pharmacologic action; |
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Phase 2 usually involves controlled trials in a limited
patient population to: |
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evaluate preliminarily the efficacy of the drug for specific,
targeted conditions, |
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determine dosage tolerance and appropriate dosage, and |
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identify possible adverse effects and safety risks; and |
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Phase 3 trials generally further evaluate clinical efficacy
and test further for safety within an expanded patient
population. |
Phase 1, 2, and 3 testing may not be completed successfully
within any specified period, or at all. We, an Institutional
Review Board, or the FDA, may suspend or terminate clinical
trials at any time on various grounds, including a finding that
the patients are being exposed to an unacceptable health risk.
The results of the preclinical and clinical studies, together
with other detailed information, including information on the
manufacture and composition of the product, are submitted to the
FDA as part of an NDA for approval prior to the marketing and
commercial shipment of the product. In most cases, the NDA must
be accompanied by a substantial user fee. The FDA also will
inspect the manufacturing facility used to produce
13
the product for compliance with cGMPs. The FDA may deny a new
drug application if all applicable regulatory criteria are not
satisfied or may require additional clinical, toxicology or
manufacturing data. Even after an NDA results in approval to
market a product, the FDA may limit the indications or place
other limitations that restrict the commercial application of
the product. After approval, some types of changes to the
approved product, such as adding new indications, manufacturing
changes and additional labeling claims, are subject to further
FDA review and approval. The FDA may withdraw product approval
if compliance with regulatory standards is not maintained or if
safety problems occur after the product reaches the market. In
addition, the FDA requires surveillance programs to monitor the
consistency of manufacturing and the safety of approved products
that have been commercialized. Holders of an approved NDA are
required to report certain adverse reactions and production
problems to the FDA to provide updated safety and efficacy
information and to comply with requirements concerning
advertising and promotional labeling. The agency has the power
to require changes in labeling or to prevent further marketing
of a product based on new data that may arise after
commercialization. Also, new federal, state, or local government
requirements may be established that could delay or prevent
regulatory approval of our products under development.
We will also be subject to a variety of foreign regulations
governing clinical trials and sales of our products. Whether or
not FDA approval has been obtained, approval of a product by the
comparable regulatory authorities of foreign countries must be
obtained prior to the commencement of marketing of the product
in those countries. The approval process varies from country to
country and the time may be longer or shorter than that required
for FDA approval. For marketing outside the U.S., we are also
subject to foreign regulatory requirements governing human
clinical trials. The requirements governing the conduct of
clinical trials, product licensing, approval, pricing, and
reimbursement vary greatly from country to country.
In addition to regulations enforced by the FDA, we are also
subject to regulation under the Occupational Safety and Health
Act, the Toxic Substances Control Act, the Resource Conservation
and Recovery Act, and other present and potential future
federal, state, or local regulations. Our research and
development activities involve the controlled use of hazardous
materials, chemicals and various radioactive compounds. Although
we believe that our safety procedures for handling and disposing
of such materials comply with the standards prescribed by state
and federal regulations, the risk of accidental contamination or
injury from these materials cannot be completely eliminated. In
the event of such an accident, we could be held liable for any
damages that result and any such liability could exceed our
resources.
Manufacturing
We were a party to a supply agreement with Avecia Biotechnology,
which was formally known as Boston Biosystems Inc., under which
we purchased our requirements for oligonucleotide compounds from
Avecia at a preferential price, which expired in March 2004. We
have continued to purchase all of the oligonucleotides we are
using in our ongoing clinical trials and pre-clinical testing
from Avecia. The terms of the agreement have been extended until
such time as a new agreement is negotiated. We expect that we
will enter into a longer term arrangement with Avecia or new
arrangements with other third-party manufacturers to supply us
with the oligonucleotide compounds that we need for our
research, preclinical, clinical and if we receive approval of a
product, commercial supply purposes.
Competition
We expect that our product candidates will address several
different markets defined by the potential indications for which
these product candidates are developed and ultimately approved
by regulatory authorities. For several of these indications,
these product candidates will be competing with products and
therapies either currently existing or expected to be developed,
including IMO-like compounds and antisense oligonucleotides
developed by third parties. Many of these existing products and
therapies are marketed by large pharmaceutical companies, have
recognized brand names and are widely accepted by physicians and
patients.
Competition among these products and therapies will be based,
among other things, on product efficacy, safety, reliability,
availability, price, and patent position.
14
The timing of market introduction of our products and
competitive products will also affect competition among
products. We also expect the relative speed with which we can
develop products, complete the clinical trials and approval
processes and supply commercial quantities of the products to
the market to be an important competitive factor. Our
competitive position will also depend upon our ability to
attract and retain qualified personnel, to obtain patent
protection or otherwise develop proprietary products or
processes and to secure sufficient capital resources for the
often substantial period between technological conception and
commercial sales.
There are a number of companies, both privately and publicly
held, that are conducting research and development, preclinical
and clinical and commercial activities relating to technologies
and products that are similar to our technologies and products,
including large pharmaceutical companies with programs in CpG
DNA compounds that have a similar mechanism of action to our IMO
compounds or in antisense technology and biotechnology companies
with similar programs. Our principal competitors include Isis
Pharmaceuticals, Inc., Genta Inc., Coley Pharmaceutical Group
and Dynavax Technologies Corp.
The primary indications for which we are developing our
antisense and IMO products are cancer and infectious diseases.
None of our competitors is currently marketing any antisense or
IMO-like product for cancer or infectious diseases, except for
Isis which is currently marketing an antisense product for the
treatment of cytomegalovirus retinitis in patients with AIDS.
However, our competitors are developing a number of product
candidates for cancer and infectious diseases that are currently
in clinical trials.
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Isis has seven antisense compounds presently in clinical trials. |
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Genta is in late-stage clinical trials for an oligonucleotide
compound for the treatment of various cancers. |
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Dynavax has a CpG DNA compound in clinical trials for four
indications. These indications include the treatment of cancer,
asthma/allergy and infectious disease. |
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Coley has two CpG DNA compounds in clinical trials for three
indications. These indications include treatment of cancer,
asthma/allergy and infectious disease. |
Many of our competitors, particularly the pharmaceutical and
biotechnology companies with which we compete, have
substantially greater financial, technical and human resources
than we have. In addition, many of our com