OUR PRODUCTS UNDER DEVELOPMENT
We have core scientific expertise in the cellular and molecular pharmacology
underlying central nervous system and cardiovascular disorders, which has
allowed us to develop product candidates for the treatment of central nervous
system, cardiovascular and urological disorders. We have five product candidates
in clinical development and four compounds in preclinical development to treat
disorders in one or more of these therapeutic areas.
CENTRAL NERVOUS SYSTEM DISORDERS
INSOMNIA AND ANXIETY
Most drugs currently marketed to treat insomnia and anxiety target the
neurotransmitter gamma-aminobutryic acid, or GABA. Neurotransmitters are
chemicals in the central nervous system that either
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excite or inhibit neuronal function. GABA is one of the principal
neurotransmitters in the central nervous system. As a result, drugs acting on
GABA receptors can produce a range of pharmacological actions.
Benzodiazepines, or BDZs, such as Valium, Librium and Xanax, target a subset
of GABA receptors commonly referred to as GABA(A) receptors. BDZs have enjoyed
widespread commercial success for over 40 years for the treatment of anxiety,
insomnia and epilepsy. In addition to their desired therapeutic effects,
however, BDZs are known to produce a variety of undesired side effects. For
example, when used to treat anxiety, these side effects can include sedation,
muscular incoordination, memory impairment and potentially lethal effects when
used with alcohol. BDZs also produce tolerance, physical dependence and can
potentially be abused.
For many years, our senior management team has conducted research on GABA(A)
receptors. Their pioneering work classified GABA(A) receptors into
biochemically, pharmacologically and functionally distinct receptor subtypes.
They demonstrated that one subset of these subtypes influences anxiety and
epilepsy, another sedation, coordination and muscle relaxation and a third
amnesia and the deleterious effects of alcohol. Furthermore, through their
research delineating the actions of BDZs on GABA(A) receptors, they were the
first to discover non-BDZ compounds that act on specific subtypes of GABA(A)
receptors.
BDZs are believed to produce their undesired side effects at therapeutic
doses because they affect all GABA(A) receptor subtypes. We believe that
compounds that act on specific GABA(A) receptor subtypes will produce the
desired therapeutic effects while eliminating or reducing the undesired side
effects associated with BDZs. For example, compounds acting at one GABA(A)
receptor subtype may reduce anxiety, while compounds acting at another GABA(A)
receptor subtype may produce sedation, in each case without the effects
associated with acting at other subtypes.
NBI-34060. NBI-34060 is our product candidate for the treatment of
insomnia. In 1998, we licensed NBI-34060 from Wyeth-Ayerst and subsequently
sublicensed it to Neurocrine, which is currently conducting a Phase III clinical
trial on this product candidate. Insomnia is defined as a persistent complaint
of difficulty in initiating or maintaining sleep, or of not feeling rested after
an otherwise adequate amount of sleep. According to the National Sleep
Foundation, approximately one-half of the adults surveyed reported trouble
sleeping at least a few nights a week in the past year, with approximately 29%
of the U.S. population reporting that they experience insomnia every night or
almost every night. IMS reported total U.S. sales of prescription drugs for the
treatment of insomnia exceeded $900 million in 2000.
In the 1980's, BDZs such as Dalmane and Halcion were extensively used to
treat insomnia. Sedation, an undesirable side effect of BDZs when used to treat
anxiety, became an intended primary therapeutic effect of BDZs to treat
insomnia. BDZs demonstrated substantial sedative effectiveness with a greater
margin of safety than previous treatments such as barbiturates. Despite the
efficacy of BDZs to treat insomnia, they produce significant undesirable side
effects, including:
- impaired motor coordination;
- confusion and memory impairment;
- rebound insomnia and anxiety after discontinuation;
- next day residual sedation;
- development of tolerance with repeated use; and
- potentially lethal effect when combined with alcohol.
Impaired motor coordination, confusion and memory impairment are especially
problematic in older patients. We believe that many of these side effects are
due to the non-selective action of BDZs on all GABA(A) receptor subtypes, as
well as their delayed onset and extended duration of action.
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A small number of non-BDZs have been introduced for the treatment of
insomnia. In March 1993, Ambien, the first and largest selling non-BDZ, was
introduced in the United States. It has shown a reduced side effect profile and
a shorter duration of action as compared to BDZs. Ambien, however, also has
undesirable side effects, including amnesia and next day residual sedation.
Despite these undesirable side effects, according to IMS figures, U.S. sales of
Ambien were approximately $712 million in 2000.
Our insomnia product candidate, NBI-34060, is a non-BDZ that is reported to
be more potent than currently marketed non-BDZs, including Ambien, and more
selectively targets the specific GABA(A) receptor subtype believed to be
responsible for promoting sleep. Furthermore, Neurocrine has noted that, in
their Phase II clinical studies, NBI-34060 was devoid of next day residual
sedation, and they expect it to have a considerably reduced amnestic potential.
We believe that NBI-34060's greater selectivity and improved pharmacokinetic
profile are responsible for its reduced side effects when compared to currently
marketed products.
Neurocrine is currently developing both an immediate release formulation and
a modified release formulation of NBI-34060 to address the different needs of
the insomnia patient population. Neurocrine's clinical studies have shown that
patient blood levels of NBI-34060 reach their highest point approximately 30
minutes after ingestion followed by rapid removal from the blood stream to the
point that it cannot be detected four hours later. This results in rapid sleep
onset followed by rapid removal of the drug from the body, reducing the risk of
next day residual sedation. Neurocrine believes that this short duration of
action will permit bedtime dosing for people who have trouble falling asleep,
and dosing in the middle of the night for people who have trouble staying
asleep, without causing the side effects and next day residual sedation that
occur with longer-acting drugs like Ambien. Neurocrine has formulated the drug
in a modified release form that will effectively provide within one tablet two
doses of the drug, one dose released immediately for sleep induction and one
dose released later for sleep maintenance.
Neurocrine has completed 19 Phase I and Phase II clinical trials of
NBI-34060 for efficacy and safety involving more than 1,100 subjects. Its
current Phase III program is reported to involve approximately 3,500 additional
subjects in eight large clinical trials. The first Phase III clinical trial,
which commenced in November 2001, involves approximately 500 patients to
evaluate an immediate release formulation of NBI-34060 for the long-term
treatment of chronic insomnia. In March 2002, Neurocrine announced that it is
initiating three additional Phase III clinical trials to evaluate the same
formulation of NBI-34060, which will involve over 1,200 patients. One of these
clinical trials will evaluate NBI-34060 for the treatment of transient insomnia.
In reported Phase II clinical studies, NBI-34060 was shown to be safe and
effective in helping patients with both chronic insomnia and transient insomnia
fall asleep rapidly without adverse side effects. Neurocrine's reported results
demonstrated that its immediate release formulation of NBI-34060 does not lead
to next day residual sedation, while both Ambien and zopiclone exhibited
statistically significant measures of next day residual sedation. In
Neurocrine's Phase II clinical trials in elderly patients, NBI-34060 was found
to be well tolerated and without next day residual sedation. Neurocrine has also
reported that its modified release formulation of NBI-34060 demonstrated
positive results in a number of sleep measures with no next day residual
sedation at doses likely to be used clinically.
The preceding description of Neurocrine's clinical development of NBI-34060
is based on their public disclosures.
OCINAPLON. Ocinaplon is our product candidate for the treatment of anxiety
disorders, including generalized anxiety disorder, or GAD, the first indication
for which we intend to seek FDA approval. Anxiety can be defined in broad terms
as a state of unwarranted or inappropriate worry and is made up of various
disorders, including GAD, panic disorder and phobias. IMS reported that in 2000,
over $1.4 billion was spent in the United States on anti-anxiety drugs,
exclusive of antidepressants. In
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addition, IMS reported that BuSpar, a non-BDZ, accounted for 50% of total U.S.
sales for anti-anxiety drugs in 2000.
BDZs such as Xanax, Librium and Valium, the non-BDZ BuSpar and
antidepressants such as Zoloft and Paxil are currently used to treat GAD and
other anxiety disorders. Each of these therapeutics, however, has problems
associated with its use. As noted above, BDZs produce significant side effects
such as impaired motor coordination, next day residual sedation, physical
dependence and potential lethal effect when mixed with alcohol. These side
effects make them less desirable treatments for anxiety, particularly for the
treatment of GAD, when long-term usage is needed. While BuSpar is non-sedating
and displays no withdrawal effects or abuse potential, its efficacy has been
reported to be relatively low, particularly in patients who have previously used
BDZs. Additionally, BuSpar takes three to six weeks of drug administration to
achieve any clinically significant reduction in anxiety, requires termination of
BDZ therapy 30 days before initiating treatment and has its own side effects
such as dizziness and nausea. Because of these issues, physicians continue to
prescribe BDZs for the treatment of anxiety. Like BuSpar, the efficacy of
antidepressants in relieving anxiety is relatively low, and several weeks of
treatment are required to achieve clinically meaningful relief. In addition,
antidepressants display their own side effects, including nervousness,
agitation, insomnia and sexual dysfunction.
We believe ocinaplon, a non-BDZ, addresses significant unmet needs for the
treatment of anxiety disorders. Ocinaplon appears to selectively modulate a
specific subset of GABA(A) receptors that we believe are involved in the
mediation of anxiety. Preclinical studies have demonstrated that ocinaplon
produces an anti-anxiety effect at doses 20 to 40 times lower than doses that
produce sedation and muscle relaxation, and 10 times lower than doses that
produce amnesia. In preclinical studies, ocinaplon was also shown to be 15 times
less likely than Valium to increase the effects of alcohol. By contrast, BDZs
often produce these side effects at doses approximating those that produce an
anti-anxiety effect.
To date, through our joint venture with Elan, we have completed eight
clinical trials on ocinaplon, including seven double-blind, placebo-controlled
Phase I trials in which over 140 healthy volunteers have participated. In these
clinical trials, ocinaplon was shown to be safe and well tolerated at the
maximum doses used, with no evidence of sedation or any other side effects
typically associated with BDZs.
In our Phase II double-blind, placebo-controlled clinical trial, ocinaplon
exhibited the following characteristics:
- efficacy at least comparable to what has been reported for BDZs;
- rapid onset of action;
- a favorable side effect profile not significantly different from placebo;
and
- no "rebound" anxiety following treatment cessation.
This Phase II clinical trial investigated the effects of an immediate
release formulation of ocinaplon on 60 GAD patients. In this clinical trial,
ocinaplon demonstrated a highly statistically significant reduction of anxiety
during the four-week study period using a number of anxiety measurements,
including the Hamilton Anxiety Scale. In addition, statistically significant
effects were measured as early as one week after treatment, a much shorter
period than reported results for current treatments. The incidence of side
effects did not differ significantly from placebo.
In December 2001, we initiated a second Phase II clinical trial. This
multicenter trial will involve 200 patients and is a 14-day double-blind,
placebo-controlled clinical trial designed to demonstrate the efficacy of
ocinaplon in patients with GAD. In this clinical trial, we are evaluating a
controlled release formulation of ocinaplon utilizing Elan's proprietary
technology.
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PAIN
BICIFADINE. Bicifadine is our product candidate for the treatment of pain.
Drugs for the treatment of pain, or analgesics, have historically been placed
into one of three general categories:
- narcotics like morphine, codeine, Demerol, and Percodan;
- non-narcotic prostaglandin inhibitors like aspirin, acetaminophen,
ibuprofen and COX-2 inhibitors; and
- other analgesics such as Ultram.
While drugs in all three of these categories are regularly used in the
treatment of pain, their use has been limited because of various side effect
profiles. In addition, administering these drugs for extended durations has been
problematic. Although prostaglandin inhibitors have been used for the treatment
of pain, particularly pain associated with inflammation, their efficacy is
limited to milder types of pain and they often display undesirable side effects
relating to the gastrointestinal tract and the liver. Narcotics are also used to
treat pain, but tolerance develops rapidly and higher doses eventually lead to
physical dependence and additional side effects, including respiratory
depression. Ultram, originally thought to be a non-narcotic, has been reported
to act at certain opiate receptors and has the potential to cause morphine-like
psychic and physical dependence. Despite these drawbacks, according to IMS, U.S.
sales in 2000 of narcotic and non-narcotic analgesics, including Ultram,
exceeded $4.6 billion.
Alternative strategies for identifying potentially novel analgesics include
altering certain neurotransmitter systems involved in mediating the sensation of
pain. Preclinical studies have implicated the neurotransmitters glutamate,
norepinephrine and serotonin in pain reduction. Treatments that interfere with
certain glutamate receptors or that increase the actions of norepinephrine and
serotonin have been reported to produce analgesic effects in animals.
Bicifadine is a chemically distinct molecule with a unique profile of
pharmacological activity. It has two primary biochemical actions. It interferes
with the ability of glutamate to stimulate calcium entry into neurons by binding
to one of its receptors on the neuron's surface. In addition, it enhances and
prolongs the actions of norepinephrine and serotonin by inhibiting the transport
proteins that terminate their physiological actions. Preclinical studies and
clinical trials indicate that any of these individual actions or a combination
of these actions may account for the analgesic properties of bicifadine.
Bicifadine is not a narcotic and in preclinical studies it has been shown
not to act at any opiate receptor. In animal models, bicifadine did not
demonstrate abuse, addiction or dependence potential. There have been four Phase
I clinical trials and 14 Phase II clinical trials involving over 1,000 patients
conducted by Wyeth-Ayerst or us with an immediate release formulation of
bicifadine. In five double-blind, placebo-controlled Phase II clinical trials,
bicifadine demonstrated a statistically significant reduction in pain, in some
cases comparable to or better than positive controls such as codeine.
Recently, we began a Phase II clinical trial in the United States studying
our new controlled release formulation of bicifadine. This 750-patient
double-blind, placebo-controlled study will compare bicifadine and codeine to
placebo in a severe dental pain model. Enrollment for this study began in
December 2001. Depending upon the results of this trial, we intend to initiate a
Phase III clinical trial program by the end of 2002. If ultimately approved,
bicifadine would not be limited to use in the pain models studied, but according
to FDA guidelines could, be used to treat pain generally.
DEPRESSION
DOV 216,303. DOV 216,303, our lead product candidate for the treatment of
depression, is a triple uptake inhibitor affecting the neurotransmitters
norepinephrine, serotonin and dopamine. These neurotransmitters regulate
numerous functions in the central nervous system, and imbalances in them have
been linked to a number of psychiatric disorders, including depression. The
actions of these neurotransmitters are terminated by specific transport proteins
that remove them from synapses in the
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brain. Antidepressants are thought to produce their therapeutic effects by
inhibiting the uptake activity of one or more of these transport proteins,
effectively increasing the concentration of these neurotransmitters at their
receptors.
The emergence of selective serotonin reuptake inhibitors, or SSRIs, starting
with Prozac in January 1988, followed by Zoloft in February 1992 and Paxil in
January 1993, has had a dramatic impact on the antidepressant market. According
to IMS figures, sales of antidepressants in the United States increased from
approximately $424 million in 1987, the year prior to the introduction of
Prozac, to approximately $9.6 billion in 2000. Despite this widespread
commercial success, SSRIs suffer from the following limitations:
- 30% - 40% of patients do not experience an adequate therapeutic response;
- three or more weeks of therapy are often required before a meaningful
improvement is observed; and
- side effects such as nervousness, agitation, insomnia and sexual
dysfunction have been documented.
Dual uptake inhibitors, like Effexor, block the uptake of serotonin and
norepinephrine. While more effective than SSRIs, dual uptake inhibitors have
their own unique set of side effects, including nausea, headache, sleepiness,
dry mouth and dizziness.
No currently marketed antidepressants inhibit the uptake of all three
neurotransmitters linked to depression. Both preclinical studies and clinical
trials indicate that a drug inhibiting uptake of serotonin, norepinephrine and
dopamine would be expected to produce a faster onset of action and greater
efficacy than traditional antidepressants. We believe that such a "broad
spectrum" antidepressant would represent a breakthrough in the treatment of
depression.
In preclinical studies, DOV 216,303 was shown to potently inhibit the uptake
of all three neurotransmitters, serotonin, norepinephrine and dopamine. In
animal models highly predictive of antidepressant action, DOV 216,303 was more
potent than both Tofranil, a dual uptake inhibitor, and Prozac. In one of these
models designed to test the onset of activity, DOV 216,303 produced an
antidepressant-like action after one week of treatment, compared to four weeks
for Tofranil. Because of its ability to inhibit the uptake of all three
neurotransmitters implicated in depression, we believe DOV 216,303 may be more
effective and have a more rapid onset than other antidepressants.
We recently completed a dose-escalating, placebo-controlled, double-blind
Phase I clinical trial in France that evaluated the blood levels and side effect
profile produced by single doses of DOV 216,303. DOV 216,303 was rapidly
absorbed following oral administration, with blood levels proportional to the
administered dose. No adverse effects were observed after doses five to ten
times higher than the projected therapeutic doses. We intend to commence a Phase
Ib multiple dose-ranging clinical trial of DOV 216,303 by the end of April 2002. |
