Item 405 of
Regulation S-K is not contained herein, and will not be contained, to the
best
of 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. ¨
Indicate
by check mark whether the registrant is a large accelerated filer, an
accelerated filer, or a non-accelerated filer.
|
Large
accelerated filer ¨
|
Accelerated
filer ¨
|
Non-accelerated
filer x
|
Indicate
by check mark whether the registrant is a shell company (as defined in Rule
12b-2 of the Exchange Act). Yes ¨ No ý
The
aggregate market value of the voting common stock held by non-affiliates
of the
registrant based upon the average of the bid and asked price on the OTC Bulletin
Board as of March 30, 2007, the last business day of the registrant’s most
recently completed second fiscal quarter, was approximately $6,600,000. Shares
of common stock held by each executive officer and director and by each other
stockholder who owned 10% or more of the outstanding common stock as of such
date have been excluded in that such stockholder might be deemed to be
affiliates. This determination of affiliate status might not be conclusive
for
other purposes.
As
of
December 10, 2007, the registrant had outstanding 31,952,749 shares of common
stock and 475,087 shares of preferred stock.
DOCUMENTS
INCORPORATED BY REFERENCE
Portions
of the Company’s definitive Proxy Statement to be filed pursuant to Regulation
14A for the registrant’s 2007 Annual Meeting of Stockholders to be held on or
about March 27, 2008 are incorporated herein by reference into Part III
hereof.
AEOLUS
PHARMACEUTICALS, INC.
ANNUAL
REPORT ON FORM 10-K
Table
of Contents
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PART
I
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Item
1A.
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Item
1B.
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Item
2.
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Item
3.
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Item
4.
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PART
II
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Item
5.
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Item
6.
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Item
7.
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Item
7A.
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Item
8.
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Item
9.
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Item
9A.
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Item
9B.
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PART
III
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Item
10.
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Item
11.
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Item
12.
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Item
13.
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Item
14.
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PART
IV
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Item
15.
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PART
I
NOTE
REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K contains forward-looking statements within the
meaning of Section 27A of the Securities Act of 1933, as amended, and Section
21E of the Securities Exchange Act of 1934, as amended, that relate to future
events or our future financial performance. You can identify forward-looking
statements by terminology such as “may,” “might,” “will,” “could,” “should,”
“would,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “predict,”
“intend,” “potential” or “continue” or the negative of these terms or other
comparable terminology. Our actual results might differ materially from any
forward-looking statement due to various risks, uncertainties and contingencies,
including but not limited to those identified in Item 1A entitled “Risk Factors”
beginning on page 18 of this report, as well as those discussed in our other
filings with the Securities and Exchange Commission and the
following:
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·
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our
need for, and our ability to obtain, additional
funds;
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·
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uncertainties
relating to clinical trials and regulatory reviews and
approvals;
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·
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our
dependence on a limited number of therapeutic
compounds;
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·
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the
early stage of the product candidates we are
developing;
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·
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the
acceptance of any future products by physicians and
patients;
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·
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competition
with and dependence on collaborative
partners;
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·
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loss
of key consultants, management or scientific
personnel;
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·
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our
ability to obtain adequate intellectual property protection and
to enforce
these rights; and
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·
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our
ability to avoid infringement of the intellectual property rights
of
others.
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Although
we believe that the expectations reflected in the forward-looking statements
are
reasonable, we cannot guarantee future results, levels of activity, performance
or achievements. We disclaim any intention or obligation to update or revise
any
forward-looking statements, whether as a result of new information, future
events or otherwise.
General
Aeolus
Pharmaceuticals, Inc. (“we” or the “Company”), a Southern California-based
biopharmaceutical company, is developing a new class of catalytic antioxidant
compounds for diseases and disorders of the central nervous system, respiratory
system, autoimmune system and oncology. Our initial target applications
are for the side effects of mustard gas exposure, cancer radiation therapy
and
amyotrophic lateral sclerosis, also known as “ALS” or “Lou Gehrig’s
disease.” We have reported positive safety results from two Phase I
clinical trials of AEOL 10150, our lead drug candidate, with no serious adverse
events noted.
We
were
incorporated in the State of Delaware in 1994. Our common stock trades on
the
OTC Bulletin Board under the symbol “AOLS.” Our principal executive offices are
located at 23811 Inverness Place, Laguna Niguel, California 92677, and our
phone number at that address is (949) 481-9825. Our website address is
www.aeoluspharma.com. However, the information on, or that can be accessed
through, our website is not part of this report. We also make available free
of
charge through our website our most recent annual report on Form 10-K, quarterly
reports on Form 10-Q, current reports on Form 8-K, and any amendments to
those
reports, as soon as reasonably practicable after such material is electronically
filed with or furnished to the SEC.
Aeolus’
Catalytic Antioxidant Program
The
findings of research on natural antioxidant enzymes and antioxidant scavengers
support the concept of antioxidants as a broad new class of pharmaceuticals
if
certain limitations noted below could be overcome. We established our research
and development program to explore and exploit the therapeutic potential
of
small molecule catalytic antioxidants. We have achieved our initial research
objectives and have begun to extend our preclinical accomplishments into
our
clinical trials.
Our
catalytic antioxidant program is designed to:
●
Retain the catalytic mechanism and high antioxidant efficiency of
the
natural enzymes, and
●
create and develop stable and small molecule antioxidants without the
limitations of superoxide dismutases (“SOD”) so that they:
●
have broader antioxidant activity,
●
have better tissue penetration,
●
have a longer life in the body, and
●
are not proteins, which are more difficult and expensive to
manufacture.
We
have
created a class of small molecules that consume free radicals catalytically;
that is, these molecules are not themselves consumed in the
reaction. Our class of compounds is a group of
manganoporphyrins (an anti-oxidant containing manganese) that retain the
benefits of antioxidant enzymes, are active in animal models of disease and,
unlike the body’s own enzymes, have properties that make them suitable drug
development candidates. Our most advanced compound, AEOL 10150, has
shown efficacy in a variety of animal models, including ALS, stroke, radiation
injury, pulmonary diseases, and diabetes. We filed an Investigational New
Drug
Application (“IND”) for AEOL 10150 in April 2004 under which clinical
trials were conducted as more fully described below under the heading “AEOL
10150 Clinical Development Program.” For a more detailed description
of antioxidants see the section below titled “Background on
Antioxidants.”
AEOL
10150
Our
lead
drug candidate is AEOL 10150 and is the first in our class of catalytic
antioxidant compounds to enter clinical evaluation. AEOL 10150 is a small
molecule catalytic antioxidant that has shown the ability to scavenge a broad
range of reactive oxygen species, or free radicals. As a catalytic antioxidant,
AEOL 10150 mimics and thereby amplifies the body’s natural enzymatic systems for
eliminating these damaging compounds. Because oxygen-derived free radicals
are
believed to have an important role in the pathogenesis of many diseases,
we
believe that Aeolus’ catalytic antioxidants and AEOL 10150 may have a broad
range of potential therapeutic uses. In particular, our catalytic antioxidants
have been shown to significantly reduce tissue damage in animal models of
ALS,
radiation therapy, mustard gas exposure, stroke and chronic obstructive
pulmonary disease for which we have focused on mustard gas exposure, radiation
therapy and ALS. However, further development of AEOL 10150 in
radiation therapy and ALS will be dependent on the results of our ongoing
study
of AEOL 10150 for the treatment of mustard gas exposure.
AEOL
10150 in Radiation Therapy
According
to the American Cancer Society, cancer is the second leading cause of death
by
disease representing one out of every four deaths in the United States with
an
expected 560,000 Americans expected to die of cancer in 2007. In
2007, nearly 1.4 million new cancer cases are expected to be diagnosed in
the
United States. The National Institutes of Health (“NIH”) estimates
overall costs of cancer in 2006 in the United States at $206.3 billion: $78.2
billion for direct medical costs, $17.9 billion for indirect morbidity costs
and
$110.2 billion for indirect mortality costs.
Combinations
of surgery, chemotherapy and radiation treatments are the mainstay of modern
cancer therapy. Success is often determined by the ability of patients to
tolerate the most aggressive, and most effective, treatment regimens.
Radiation therapy-induced toxicity remains a major factor which limits the
ability to escalate radiation doses in the treatment of tumors. The ability
to deliver optimal radiation therapy for treatment of tumors without injury
to surrounding normal tissue has important implications in oncology because
higher doses of radiation therapy may improve both local tumor control and
patient survival. Advances in the tools of molecular and cellular biology
have enabled researchers to develop a better understanding of the
underlying mechanisms responsible for radiation therapy-induced normal
tissue injury. For decades ionizing radiation has been known to increase
production of free radicals, which is reflected by the accumulation of
oxidatively damaged cellular macromolecules. As one example of
radiation-induced damage to adjacent normal tissue, radiation therapy may
injure
pulmonary tissue either directly via generation of reactive oxygen species
(“ROS”) or indirectly via the action on parenchymal and inflammatory cells
through biological mediators such as transforming growth factor beta (TGF
B) and
pro-inflammatory cytokines. Since the discovery of SOD, it has become clear
that these enzymes provide an essential line of defense against
ROS. SODs and SOD mimics, such as AEOL 10150, act by catalyzing the
degradation of superoxide radicals into oxygen and hydrogen
peroxide. SODs are localized intra/extracellularly, are widely
expressed throughout the body, and are important in maintenance of redox
status
(the balance between oxidation and reduction). Previous studies have
demonstrated that treating irradiated animal models with SOD delivered by
injection of the enzyme through liposome/viral-mediated gene therapy or
insertion of human SOD gene can ameliorate radiation
therapy-induced damage. For an illustrative example of the
radiation therapy reaction see Figure 1 below.
Figure
1 above shows the dual mechanism of action of radiation therapy and
the
application of AEOL 10150 to the process.
In
vitro
studies have demonstrated that AEOL 10150 reduces the formation of lipid
peroxides and that it inactivates biologically important ROS molecules such
as superoxide, hydrogen peroxide, and peroxynitrite. AEOL 10150 inactivates
these ROS by one or two electron oxidation or reduction reactions in which
the oxidation state of the manganese moiety in AEOL 10150 changes. AEOL
10150 is not consumed in the reaction and it continues to inactivate such
ROS molecules as long as it is present at the target site.
A
number
of preclinical studies by Zjelko Vujaskovic, MD, PhD; Mitchell Anscher, MD,
et
al of Duke University. have demonstrated the efficacy of
AEOL 10150 in radioprotection of normal tissue. Chronic administration
of AEOL 10150 by continuous, subcutaneous infusion for 10 weeks has demonstrated
a significant protective effect from radiation-induced lung injury in rats.
Female Fisher 344 rats were randomly divided into four different
dose groups (0, 1, 10 and 30 mg/kg/day of AEOL 10150), receiving either
short (one week) or long-term (ten weeks) drug administration via osmotic
pumps. Animals received single dose radiation therapy of 28 Gray (“Gy”) to
the right hemithorax. Breathing rates, body weights, histopathology
and immunohistochemistry were used to assess lung damage. For the long
term administration, functional determinants of lung damage 20 weeks
post-radiation were significantly decreased by AEOL 10150. Lung
histology at 20 weeks revealed a significant decrease in structural damage
and fibrosis. Immunohistochemistry demonstrated a significant reduction
in macrophage accumulation, collagen deposition and fibrosis, oxidative
stress and hypoxia in animals receiving radiation therapy along with
AEOL 10150. There were no significant differences between the
irradiated controls, and the 3 groups receiving short-term administration
of AEOL 10150 and single dose radiation therapy. Figure 2
below shows a semi-quantitative analyses of lung histology at 20 weeks which
revealed a significant decrease in structural damage and its severity in
animals receiving 10 and 30 mg/kg/day after radiation in comparison to
radiation therapy along with placebo group or radiation therapy along with
1
mg/kg of AEOL 10150 (p = 0.01).
Figure
2 above show that AEOL 10150 treatment decreases
the severity of damage and increases the percentage of lung tissue with no
damage from radiation therapy in a study by Zjelko Vujaskovic, MD, PhD; Mitchell
Anscher, MD, et al of Duke University.
Two
additional studies examining the effect of subcutaneous injections of AEOL
10150
on radiation-induced lung injury in rats have been completed. The
compound was administered subcutaneously by a bid dosing regime (i.e. 2.5
mg/kg
or 5.0 mg/kg) on the first day of radiation and daily for five consecutive
weeks. Radiation was fractionated rather than single dose, with 40 Gy
divided in five 8 Gy doses. Preliminary immunohistologic analyses of the
lung tissue from these two studies showed a dose dependent decrease in
the inflammatory response quantified by the number of activated macrophages
or areas of cell damage.
These
in
vivo studies employing subcutaneous administration of AEOL 10150, either
by continuous infusion via osmotic pump or bid injection, demonstrate that
AEOL 10150 protects healthy lung tissue from radiation injury delivered
either in a single dose or by fractionated radiation therapy doses. AEOL
10150 mediates its protective effect(s) by inhibiting a number of events in
the inflammatory cascade induced by radiation damage. Additional in vivo
studies have been performed that provide support for
manganoporphyrin antioxidant protection of lung tissue from radiation.
Treatment with a related manganoporphyrin compound, AEOL
10113 significantly improved pulmonary function, decreased histopathologic
markers of lung fibrosis, decreased collagen (hydroxyproline) content,
plasma levels of the profibrogenic cytokine,
transforming growth factor beta (TGF-β) and, as demonstrated
by immunohistochemistry
of lung
tissue, collagen deposition and TGF-β.
An
important consideration for the use of an antioxidant in radioprotection
of
normal adjacent tissue is the potential interference with the efficacy of
tumor radiotherapy. A number of preclinical in vivo studies have addressed
this issue and have demonstrated that AEOL 10150 does not negatively affect
tumor radiotherapy.
In
one
study (Vujaskovic, et al. of Duke University), human prostate tumors
(PC3) grown in nude mice to substantial size were fraction irradiated with
5 Gy per day for 3 days for a total of 15 Gy. AEOL 10150 at 7.5 mg/kg/bid
was administered subcutaneously on the first day of radiation and continued
for either of two time courses: when tumor volume reached 5 times the
initial volume or for twenty days. The receding tumor volume curves
for irradiation only and for irradiation plus AEOL 10150 were
super-imposable. Therefore AEOL 10150 did not interfere with the radiation
effect on xenogenic prostate tumor.
Figure
3. Relative tumor volumes of human prostate tumor implants in nude
mice: Implants of well-vascularized PC3 tumors were grown to substantial
size prior to receiving fractionated radiation (5 Gy daily for three days).
AEOL 10150 (7.5 mg/kg/bid) was administered subcutaneously commencing on
the first day of irradiation and continued for 20 days. Other groups of
mice received either no irradiation, irradiation only or AEOL 10150 without
irradiation.
In
another study of prostate cancer tumors (Gridley, et al of Loma Linda
University), mouse prostate cancer cell line RM-9 was injected
subcutaneously into C57/Bl6 mice, followed by up to 16 days of AEOL 10150
delivered intraperitonealy at 6 mg/kg/day. On day seven, a single
non-fractionated dose of radiation (10 Gy) was delivered. Therefore,
the mice received compound for seven days prior to radiation. The results
of this study demonstrated that AEOL 10150 does not protect the prostate
tumor against radiation and in fact AEOL 10150 showed a trend towards
increasing the effectiveness of the radiation treatment. The primary effect
appears to be in down-regulation of radiation induced HIF-1 expression and
VEGF and up-regulation of IL-4. Thus, AEOL 10150, through its
down-regulation of VEGF, may inhibit formation of blood vessels (i.e.
angiogenisis) required for tumor regrowth and protects normal tissues from
damage induced by radiation and chemotherapy.
Figure
4 above measures tumor volume against time after
implantation of RM-9 tumor cells and shows that AEOL 10150 treatment resulted
in
inhibition of tumor re-growth in a study performed by Dr. Gridley of
Loma Linda University. Daily intraperitoneal
injections of AEOL 10150 were initiated on day 1. At 12 days, approximately
one
half of each tumor-bearing group and control mice with no tumor were
euthanized for in vitro analyses; remaining mice/group were followed for
tumor growth and euthanized individually when maximum allowed tumor volume
was attained. Each point represents the mean +/- standard error of the
mean. Two-way analysis of the variance for days 8 to 14 revealed that group
and time had highly significant main effects (Ps<0.001) and a group x
time interaction was noted (P<0.001).
Figure
5 above shows the HIF-1 Expression in prostate
tumors
and the impact of the treatment of AEOL 10150 in a study by Dr. Gridley of
Loma Linda University.
In
summary, the data obtained in these preclinical studies suggest that the
post
irradiation long term delivery of AEOL 10150 may be protective against
radiation-induced lung injury, as assessed by histopathology and
immunohistochemistry. Oxidative stress, inflammation and hypoxia,
which play important roles in the pathogenesis of radiation mediated fibrosis,
were also shown to be reduced in animals treated with higher doses of AEOL
10150. Studies have also shown that AEOL 10150 does not adversely affect
tumor response to radiation therapy. Thus, treatment with AEOL 10150
does not significantly protect tumors from the cell killing effects of radiation
therapy. This combined with other studies that have shown that AEOL
10150 significantly prevents radiation induced normal tissue injury suggests
that AEOL 10150 has the potential to achieve normal tissue protection without
protection of tumor tissue.
AEOL
10150 in Treatment of the Effects of Mustard Gas Exposure
Sulfur
mustards, of which mustard gas is a member, are a class of related cytotoxic,
vesicant chemical warfare agents with the ability to form large blisters
on
exposed skin. In their pure form most sulfur mustards are colorless, odorless,
viscous liquids at room temperature. When used as warfare agents they are
usually yellow-brown in color and have an odor resembling mustard plants,
garlic
or horseradish. Mustard agents, including sulfur mustard, are
regulated under the 1993 Chemical Weapons Convention. Three classes
of chemicals are monitored under this Convention, with sulfur and nitrogen
mustard grouped in the highest risk class, "schedule 1". However,
concerns about its use in a terrorist attack have lead to a resurgence in
research to develop a protectant against exposure.
The
increased risk of a terrorist attack in the United States involving chemical
agents has created new challenges for many departments and agencies across
the
federal government. Within the Department of Health and Human Services, the
NIH
is taking a leadership role in pursuing the development of new and improved
medical countermeasures designed to prevent, diagnose, and treat the conditions
caused by potential and existing chemical agents of terrorism. In addition,
many
of the same chemicals posing a threat as terrorist agents may also be released
from transportation and storage facilities by industrial accidents or during
a
natural disaster. The NIH has developed a comprehensive Countermeasures Against
Chemical Threats (“CounterACT”) Research Network that includes Research Centers
of Excellence, individual research projects, SBIRs, contracts and other
programs. The CounterACT network will conduct basic, translational, and clinical
research aimed at the discovery and/or identification of better therapeutic
and
diagnostic medical countermeasures against chemical threat agents, and their
movement through the regulatory process. The overarching goal of this research
program is to enhance our diagnostic and treatment response capabilities
during
an emergency.
Mustard
gas is a strong vesicant (blister-causing agent). Due to its alkylating
properties, it is also strongly mutagenic (causing damage to the DNA of exposed
cells) and carcinogenic (cancer causing). Those exposed usually suffer no
immediate symptoms. Within 4 to 24 hours the exposure develops into deep,
itching or burning blisters wherever the mustard contacted the skin; the
eyes
(if exposed) become sore and the eyelids swollen, possibly leading to
conjunctivitis and blindness. At very high concentrations, if
inhaled, it causes bleeding and blistering within the respiratory system,
damaging the mucous membrane and causing pulmonary edema. Blister agent exposure
over more than 50% body surface area is usually fatal.
Researchers
at National Jewish Medical & Research Center and the University of Colorado
Health Sciences in Denver, Colorado have been awarded a five year Center
grant
from the NIH CounterACT Research Network to support the development of compounds
to protect and treat lung and skin injury associated with mustard gas
exposure. One of the lead compounds being tested in these
studies is AEOL 10150.
Research
in the area of mustard gas-mediated lung injury has provided experimental
evidence that the mechanisms of these injuries are directly linked to the
formation of reactive oxygen and nitrogen species and that superoxide dismutase
and catalase can ameliorate injury responses. This theory has led to the
hypothesis that the administration of catalytic antioxidant therapy can protect
against mustard gas-induced acute lung and dermal injury. AEOL 10150 has
already
been shown to be well tolerated in humans and could be rapidly developed
towards
a NDA pending animal efficacy data.
Recent
studies have found that the chemical warfare agent analog, 2-chloroethyl
ethyl
sulfide (“CEES”)-induced lung injury could be ameliorated by both exogenous
superoxide dismutase and catalase. Both of these natural enzymes are important
catalytic antioxidants and both these reactions are exhibited by
metalloporphyrins. CEES-induced lung injury is dependent in part upon
blood neutrophils. Activated neutrophils are an important source of reactive
oxygen species that are known to contribute to lung injury
responses. Antioxidants have also been shown to protect against
CEES-induced dermal injury. Mustard exposure is often associated with
producing adult respiratory distress syndrome (“ARDS”) that requires
supplemental oxygen therapy to maintain adequate tissue
oxygenation.
Preliminary
studies suggest that AEOL 10150 at 5/mg/kg, sc dose can rescue acute lung
injury
responses when dosed 1 hour after the sulfur mustard gas analog exposure.
The
next steps are to determine whether this protective effect still occurs with
authentic mustard gas and whether the compound can also provide protection
against the chronic lung fibrotic effects of mustard gas exposures. These
data
suggest that AEOL 10150 may provide an effective countermeasure to mustard
gas
attacks that can be rapidly developed.
The
goal
of the CounterACT is to assist in the development of safe and effective medical
countermeasures designed to prevent, diagnose, and treat the conditions caused
by potential and existing chemical agents of terrorism which can be added
to the
Nation’s Strategic National Stockpile (“SNS”). The SNS is maintained
by the Centers for Disease Control and Prevention (“CDC”). The SNS now contains
CHEMPACKS which are located in secure, environmentally controlled areas
throughout the United States available for rapid distribution in case of
emergency. The CDC has established a diagnostic response network for the
detection of nerve agents, mustard, cyanide and toxic metals. The NIH will
continue to research, develop and improve medical products that include chemical
antidotes, drugs to reduce morbidity and mitigate injury, drugs to reduce
secondary to chemical exposure and diagnostic tests and assessment tools
to be
used in mass casualty situations.
AEOL
10150 in ALS
ALS,
commonly referred to as “Lou Gehrig’s disease,” the most common motor neuron
disease, results from progressive degeneration of both upper and lower motor
neurons. According to the ALS Association (“ALSA”), the incidence of ALS is two
per 100,000 people. ALS occurs more often in men than women, with typical
onset
between 40 and 70 years of age. ALS is a progressive disease and approximately
80% of ALS patients die within five years of diagnosis, with only 10% living
more than 10 years. The average life expectancy is two to five years after
diagnosis, with death from respiratory and/or bulbar muscle failure. The
International Alliance of ALS/MND Associations reports there are over 350,000
patients with ALS/MND worldwide and 100,000 people die from the disease each
year worldwide. In the United States, ALSA reports that there are
approximately 30,000 patients with ALS with 5,600 new patients diagnosed
each
year.
Sporadic
(i.e., of unknown origin) ALS is the most common form, accounting for 80-90%
of
cases. The cause of sporadic ALS is unclear. Familial ALS comprises the
remainder of cases and 10-20% of these patients have a mutated superoxide
dismutase 1 (“SOD1”) gene. More than 90 point mutations have been identified,
all of which appear to associate with ALS, and result in motor neuron disease
in
corresponding transgenic mice. SOD mutations have been observed in both familial
and sporadic ALS patients, although the nature of the dysfunction produced
by
the SOD1 mutations remains unclear. The clinical and pathological manifestations
of familial ALS and sporadic ALS are indistinguishable suggesting common
pathways in both types of disease.
John
P.
Crow, Ph.D., and his colleagues at the University of Alabama at Birmingham
tested AEOL 10150 in an animal model of ALS (SOD1 mutant G93A transgenic
mice).
The experiments conducted by Dr. Crow (now at the University of Arkansas
College of Medicine) were designed to be clinically relevant by beginning
treatment only after the onset of symptoms in the animals is
observed.
Twenty-four
confirmed transgenic mice were alternately assigned to either a control group
or
AEOL 10150-treatment on the day of symptom onset, which was defined as a
noticeable hind-limb weakness. Treatment began on the day of symptom onset.
The
initial dose of AEOL 10150 was 5 mg/kg, with continued treatment at a dose
of
2.5 mg/kg once a day until death or near death.
|
Treatment
|
|
Age
at Symptom onset mean days + SD(range)
|
|
Survival
Interval mean days + SD(range)
|
|
P-value
Log-rank (v. control)
|
|
P-value
Wilcoxon (v. control)
|
|
|
|
|
|
|
|
|
|
|
|
Control
|
104.8
+ 1.43
|
12.8
+ 0.79
|
|
|
||||
|
|
|
(100-112
|
)
|
(9-16
|
)
|
|
|
|
|
AEOL
10150
|
|
106.1
+ 1.5
|
|
32.2
+ 2.73
|
|
|
|
|
|
|
|
(100-115
|
)
|
(15-46
|
)
|
<
0.0001
|
|
0.0002
|
Table
1. Effect of AEOL 10150 on survival of G93A transgenic
mice
Figure
6.
Table
1
and Figure 6 above show that AEOL 10150 treatment resulted in a greater than
2.5
times mean survival interval, compared to control. AEOL 10150-treated mice
were
observed to remain mildly disabled until a day or two before death. In contrast,
control mice experienced increased disability daily.
Dr. Crow
has repeated the ALS preclinical experiment a total of four times, in each
case
with similar results. The efficacy of AEOL 10150 in the G93A mouse model
of ALS
has also been evaluated by two additional laboratories. One of these
laboratories verified an effect of AEOL 10150 in prolonging survival of the
G93A
mouse, while no beneficial effect of the drug was identified in the other
laboratory.
In
November 2003, the U.S. Food and Drug Administration (the “FDA”) granted orphan
drug designation for our ALS drug candidate. Orphan drug designation qualifies
a
product for possible funding to support clinical trials, study design assistance
from the FDA during development and for financial incentives, including seven
years of marketing exclusivity upon FDA approval.
AEOL
10150 Clinical Development Program
AEOL
10150 has been thoroughly tested for safety, tolerability and pharmacokinetics
with no serious or clinically significant adverse effects
observed. To date, 37 patients have received AEOL 10150 in two
clinical trials designed to test the safety and tolerability of the drug
candidate.
In
September 2005, we completed a multi-center, double-blind, randomized,
placebo-controlled, Phase I clinical trial. This escalating single dose study
was conducted to evaluate the safety, tolerability and pharmacokinetics of
AEOL
10150 administered by twice daily subcutaneous injections in patients with
ALS.
In
the
Phase Ia study, 4-5 patients diagnosed with ALS were placed in a dosage cohort
(3 or 4 receiving AEOL 10150 and 1 receiving placebo). Each dose cohort was
evaluated at a separate clinical center. In total, seven separate cohorts
were
evaluated in the study, and 25 ALS patients received AEOL 10150. Based upon
an
analysis of the data, it was concluded that single doses of AEOL 10150 ranging
from 3 mg to 75 mg were safe and well tolerated. In addition, no serious
or
clinically significant adverse clinical events were reported, nor were there
any
significant laboratory abnormalities. Based upon extensive cardiovascular
monitoring (i.e., frequent electrocardiograms and continuous Holter recordings
for up to 48 hours following dosing), there were no compound-related
cardiovascular abnormalities.
Following
administration of single doses of AEOL 10150 (3, 12, 30, 45, 60 and 75 mg),
pharmacokinetic analysis demonstrated plasma area under the curve (AUC) values
ranging from 354 ng•hr/mL in the 3 mg group to 12,167 ng•hr/mL in the 75 mg
group. Correspondingly, Cmax ranged from 114.8 ng/mL to 1584 ng/mL,
and Tmax ranged from 1 to 2 hours in these same groups. The mean half-life
of
AEOL 10150 ranged from 2.6 (3 mg cohort) to 6.4 hours (75 mg cohort). Linear
dose response and dose proportionality were documented. The Cmax measures
peak
concentration of a drug in plasma. The Tmax measures the time to the peak
plasma
concentration noted (i.e. Cmax). A summary of these results is provided in
table form below.
Pharmacokinetic
Parameters for AEOL 10150: Result Summary, Phase Ia Single Dose
Evaluation
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AEOL
10150
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Pharmacokinetic
Parameter
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3
mg N = 3
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12
mg N = 4
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30
mg N = 3
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45
mg N = 4
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45
mg
N
= 4 (repeat, different
patients)
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60
mg N = 4
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75
mg
N=
3
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AUC(0-∞)
(hr•ng/mL)
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354
±
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1,494
±
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4,580
±
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7,116
±
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5,922
±
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9,087
±
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12,167
±
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Tmax
(0-48) (hr)</ | ||||||||||||||