| Product | Indication(s) |
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Indiplon |
Insomnia |
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Insomnia (top) Insomnia is a neurological disorder with approximately 85 million adults in the U.S. reporting trouble sleeping a few nights or more per week, according to a 2005 report from Mattson Jack (an epidemiological database used to determine the prevalence of a disease or disorder). Mattson Jack also reports that approximately 22 million adults in the U.S. experience chronic insomnia, having trouble sleeping every night or almost every night. In addition, according to the National Sleep Foundation (2003), frequent sleep problems in individuals that are 55 to 84 years old, if ignored, can complicate the treatment of other medical conditions, including arthritis, diabetes, heart and lung disease and depression. According to a 2005 report from IMS Health, the U.S. insomnia pharmaceutical market was $2.2 billion in 2004 and was expected to exceed $2.7 billion in 2005. The most frequently prescribed drugs currently marketed to treat insomnia target the neurotransmitter gamma aminobutryic acid, or GABA. Neurotransmitters are chemicals in the CNS that either excite or inhibit neuronal function. GABA is the principal inhibitory neurotransmitter in the CNS. Benzodiazepines, or BDZs, target the GABAA receptors. During the 1980s, BDZs were commonly used as sedatives to treat insomnia. This class of drugs produces several undesirable side effects, including negative interactions with other CNS depressants, such as alcohol, the development of tolerance upon repeat dosing and rebound insomnia, or the worsening of insomnia following discontinuation of dosing. Additional side effects, due to the long half-life, or the duration of action, of a compound associated with this class of drugs, include next-day residual sedation effects and impairment of coordination and memory. Memory impairment, which can include amnesia for events occurring prior to and after drug administration, is of particular concern in the elderly, who comprise approximately 18 percent of the total insomnia population, according to Mattson Jack (2005). During the late 1980s, the class of drugs known as non-BDZs was developed to target a specific site on the GABAA receptor. The non-BDZs have a reduced incidence of side effects that are believed to be attributable to binding more selectively on a GABAA receptor subtype than the BDZs. The most commonly prescribed of the non-BDZs in the U.S. are Ambien®, Sonata® and Lunesta®. Ambien is the current market leader, with approximately $1.8 billion in worldwide sales in 2005, according to Sanofi-Aventis. Indiplon (top) For the treatment of insomnia Indiplon, DOV’s insomnia product candidate, is a non-BDZ shown to be more potent and fast-acting than currently marketed non-BDZs, including Ambien. In 1998, we licensed indiplon from Wyeth Holdings Corporation, or Wyeth, and sublicensed it to Neurocrine. In December 2002, Neurocrine entered into a development and commercialization agreement with Pfizer for indiplon. In June 2006, Neurocrine and Pfizer terminated their collaboration agreement for indiplon. Neurocrine is currently evaluating commerical alternatives. In all cases, we are entitled to a 3.5 percent royalty on worldwide net sales of indiplon, if any. In April 2005 and May 2005 Neurocrine submitted two indiplon NDAs, for an immediate release, or IR, capsule formulation and a modified release, or MR, tablet formulation for the treatment of insomnia. Neurocrine is developing indiplon in these two formulations, a short acting capsule and a longer acting tablet to address the different needs of the insomnia patient population. These formulations capitalize on key features of indiplon: its ability to induce sleep quickly - approximately 15 minutes after taking the pill - and its rapid elimination from the body, which essentially eliminates the next-day residual sedation effects commonly produced by other drugs of this class. In January 2006, the FDA requested and received submission of results from Neurocrine’s driving study, completed in late 2005. Based on feedback from the FDA, Neurocrine stated that it anticipated labeling that would include data from this study, which showed no impairment in next-day driving performance. The FDA stated its intent to issue a combined package insert in lieu of individual package inserts for the capsule and tablet NDAs. In May 2006, Neurocrine announced that the FDA had determined that indiplon 5 mg and 10 mg capsules were approvable and the 15 mg XR tablets were not approvable at that time. Neurocrine also stated that the FDA indicated that they did not have an opportunity to review all of the information submitted during the NDA review cycles. In June 2006, Neurocrine announced that it had completed its review of the indiplon action letters and had requested a meeting with the FDA. Neurocrine stated that feedback from this FDA meeting will help the Company determine plans in moving forward. Later that month, Neurocrine and Pfizer also announced that they had terminated their collaboration agreement for the development of indiplon. Neurocrine said that Pfizer would continue to support indiplon for a period of up to 180 days to ensure a smooth transition and that Neurocrine would reacquire full worldwide rights to this product, which, it believes, has significant commercial value. Neurocrine also stated that it would evaluate commercial alternatives throughout various worldwide markets once its resubmissions have been made. Neurocrine’s indiplon program has now successfully completed clinical trials demonstrating that indiplon capsules and tablets help patients consistently fall asleep faster, increase the amount of time they sleep during the night, decrease number of nighttime awakenings and improve overall sleep quality over the course of short or long-term treatment without evidence of tolerance when administered nightly for up to three months or withdrawal upon discontinuation of nightly dosing - complications often seen with extended use of older-generation sleep medications. Neurocrine also has noted that, in its Phase II and Phase III clinical studies, indiplon demonstrated efficacy with no significant next-day residual sedation at clinically relevant doses and showed, in a driving study, no impairment in next-day driving performance. Neurocrine’s NDAs for indiplon contain data from a total of 74 clinical trials that included approximately 8,000 adult and elderly subjects, more than 350,000 patient exposures and more than 80 preclinical studies. The data reported from these trials consistently have met both primary and secondary endpoints demonstrating the efficacy and safety of indiplon. Note: The preceding descriptions of Neurocrine’s clinical development and clinical trial results of indiplon are based on Neurocrine’s public disclosures through June 22, 2006. |
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Pain (top) Identifying the etiology of pain is essential to its management. Pain is defined as unpleasant sensory and emotional experience associated with actual or potential tissue damage discomfort. Drugs for the treatment of pain, or analgesics, have historically been placed into one of two general categories:
The FDA has granted approval for two other classes of compounds for the management of specific types of chronic pain. In the first class, Neurontin®, marketed by Pfizer, is an anticonvulsant whose actions on ion channels in neuronal tissue are likely responsible for its therapeutic effects in a certain type of neuropathic pain (postherpetic neuralgia). Sharing a similar structure with Neurontin is Lyrica®, also marketed by Pfizer, which was approved in December 2004 for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. In the second class, Cymbalta®, marketed by Eli Lilly and Co., was granted approval in September 2004 for the management of diabetic peripheral neuropathic pain. Cymbalta’s mechanism of action is believed to result from the inhibition of the uptake of serotonin and norepinephrine (SNRI) in nerve cells, properties also possessed by bicifadine. Bicifadine (top) For the treatment of pain Bicifadine, in a sustained release, or SR, formulation, is our product candidate for the treatment of pain. Bicifadine is a chemically distinct molecule with a unique profile of pharmacological activity. Its primary pharmacological action is to enhance and prolong the actions of norepinephrine and serotonin by inhibiting the transport proteins that terminate the physiological actions of the two biogenic amines. While we believe that bicifadine also possesses additional neurochemical properties that contribute to its analgesic effects, the exact nature of these other properties is under investigation. Preclinical studies and clinical trials indicate that either or a combination of these individual actions may account for the analgesic properties of bicifadine. Bicifadine is not a narcotic and, in preclinical studies, has been shown not to act at any opiate receptor. In preclinical studies to date, bicifadine has not demonstrated abuse, addiction or dependence potential, although, in a Phase I clinical trial, the immediate release, or IR, formulation did cause mild and transient euphoric mood in some subjects. Four Phase I clinical trials and 14 Phase II clinical trials involving more than 1,000 patients were conducted by Wyeth or DOV with an IR formulation of bicifadine. In five exploratory double-blind, placebo-controlled Phase II clinical trials of the IR formulation conducted by Wyeth, bicifadine demonstrated a statistically significant reduction in pain versus placebo, in some cases with an outcome suggesting it might be comparable to or better than positive controls such as codeine. In addition to these trials with the IR formulation, we have conducted eight Phase I clinical trials using the SR formulation, a formulation that permits less frequent daily dosing, improves tolerability and for which patents have been filed. We are evaluating the SR formulation in our ongoing clinical development programs and this formulation is intended for commercial use. Chronic Pain Drug Development Program In March 2004 and February 2006, we reached agreement with the FDA on a plan for the balance of the Phase III bicifadine preclinical and clinical program necessary to submit an NDA for chronic pain. The agreed upon program must include positive results from two placebo-controlled dose-response studies of three months’ treatment duration in patients with CLBP, such as the study that is currently ongoing. We also will need to obtain long-term safety observations from at least 100 CLBP patients treated with bicifadine for one year and 300 CLBP patients treated with bicifadine for six months at the maximal recommended dose, which is anticipated to be 400 mg b.i.d. The FDA did not express any particular concerns regarding the safety profile of bicifadine based on the results of preclinical and clinical testing, including observations from previously conducted clinical trials in which more than 1,500 subjects received bicifadine SR. A significant outcome of our February 2006 meeting was the FDA’s stated receptivity to review an NDA for a broad label chronic pain indication for bicifadine using the current CLBP clinical trials package provided we would commit to study bicifadine in two additional models of chronic pain in Phase IV post-approval studies, such as osteoarthritis or neuropathic pain. DOV intends to make this commitment. Phase III Chronic Pain Trials of Bicifadine In April 2006, we announced the results of a Phase III, U.S. clinical trial of bicifadine in approximately 600 patients with moderate to severe CLBP (study 020). The clinical trial was a randomized, double-blind, placebo-controlled, outpatient, multi-center study assessing the efficacy and tolerability of three dose levels of bicifadine - 200 mg, 300 mg and 400 mg b.i.d. - over a three-month period. Patients who completed the study were eligible for up to one year of additional treatment in a bicifadine open-label safety and efficacy study (study 022). The primary efficacy endpoint was the change in pain severity rating as measured by the 100 mm Visual Analog Scale, or VAS, score between baseline and the end of dosing. Despite a positive futility analysis for study 020, bicifadine did not show a statistically significant effect relative to placebo on the primary endpoint of the study at any of the doses tested. We have conducted additional analyses of the study and have now determined that an unusually high placebo response rate was the single major contributory factor to the failure of the trial. We also have identified disease severity, as defined by either the degree of functional disability or the concomitant presence of pain radiating down the leg (sciatica), as the major factor controlling the difference between patientsí response to placebo and their response to bicifadine. Our analysis shows that as disease severity worsened, placebo response decreased and the relative effect of bicifadine increased. We are using these findings to strategically amend our ongoing Phase III trial of bicifadine in CLBP patients, study 021. We currently are enrolling subjects into our second Phase III clinical trial of bicifadine in patients with moderate to severe CLBP, study 021. In May 2006, we amended the protocol for this trial to enroll only patients who meet the preferred enrollment criteria for baseline disability and/or back pain that radiates down the leg. In July 2006, we announced that we have dropped the 400 mg b.i.d. bicifadine dosing arm given the lack of increased efficacy shown with this dose over other doses in study 020. Given these amendments, study 021 is now expected to enroll a decreased number of patients and we expect to report the results of the study in the fourth quarter of 2006. We also have completed enrollment of subjects into an open-label Phase III, multi-center clinical trial to evaluate the long-term safety and efficacy of bicifadine in patients with CLBP (study 022). This clinical trial has enrolled approximately 1,200 total patients with CLBP who have been randomized to receive either 400 mg b.i.d. of bicifadine or any appropriate pharmacological analgesic treatment or treatments, or "standard of care" (SOC), selected by the investigator. The primary objective of this clinical trial is to evaluate the safety of bicifadine for up to one year in patients with CLBP. The ongoing results from study 022 suggest that bicifadine is at least as effective as SOC in treating CLBP and is safe and well-tolerated. Initial data suggest that patients receiving bicifadine “de novo” experience a decrease in pain, as measured by VAS score, from a rating of approximately 70 mm to 40 mm over the first four weeks. Further, patients who have “rolled over” from study 020 or 021 are entering the trial with an average VAS score of about 40 mm and continue to decrease their pain scores over the following weeks and months. The positive data trends are continuing, with dosing now spanning twelve months. Phase II Chronic Pain Trials In Progress In February 2006, we initiated an exploratory Phase II clinical trial of bicifadine in patients with osteoarthritis. The trial is a multi-center, double-blind, placebo-controlled, four-way crossover trial designed to assess the efficacy, tolerability and pharmacokinetics of bicifadine alone and in combination with ibuprofen. The clinical trial expects to enroll 60 patients with osteoarthritis of the hip or knee. Each patient receives one week of dosing for each of the following four treatment regimens: bicifadine, ibuprofen, bicifadine plus ibuprofen and placebo. There is a one week washout period between each of the dosing arms. Efficacy is determined using change from baseline for pain via VAS scores, the WOMAC arthritis index, patients’ global improvement assessments and other recognized measures. Preclinical studies of bicifadine show the drug has demonstrated efficacy in models of inflammatory pain. DOV expects to complete dosing for this Phase II trial in the third quarter of 2006. Acute Pain Drug Development Program In March 2004 and March 2006, DOV received guidance from the FDA on a plan for the balance of the Phase III bicifadine program necessary to submit an NDA for acute pain. The March 2006 meeting revealed that the FDA is receptive to reviewing an NDA for a broad label acute pain indication for bicifadine based on the successful outcomes from two Phase III clinical trials in repeat-dose acute pain models. This is fewer trials than expected, and there was agreement that one of these trials may be in a non-surgical pain model. This FDA guidance marks a significant improvement for the bicifadine acute pain program in terms of the regulatory path, and we will have further communication with the FDA as we determine the optimal acute pain models to pursue as part of an acute pain NDA package. Completed Acute Pain Trials of Bicifadine In August 2002, we completed a Phase II clinical trial in the U.S. involving 750 patients in the treatment of moderate to severe post-surgical dental pain. This Phase II trial was a single-dose, double-blind, placebo-controlled, study that evaluated three controlled release doses of bicifadine and one dose of codeine compared to placebo. Bicifadine produced a highly statistically significant, dose-related reduction in pain compared to placebo at each of the two higher doses. The efficacy of bicifadine was at least equivalent to codeine at all three doses. The trial demonstrated bicifadine to be safe and relatively well-tolerated without producing any serious adverse events. In September 2003, we completed a 540-patient, double-blind, placebo-controlled Phase III clinical trial to compare three doses of bicifadine and one dose of tramadol to placebo in a moderate to severe post-surgical dental pain model. Bicifadine, in a dose-dependent fashion, produced a highly statistically significant reduction in pain compared to placebo, as did the single-dose level of tramadol. Statistically significant increases in analgesia were measured as early as one hour after administration and analgesia was sustained for the balance of the six-hour measurement period. The maximal efficacy of bicifadine was statistically indistinguishable from tramadol. Both bicifadine and tramadol were safe and relatively well-tolerated without producing any serious adverse events. In September 2005, we completed a Phase III randomized, double-blind, placebo-controlled, outpatient, multi-center clinical trial to assess the efficacy and safety of three dose levels of bicifadine in patients with moderate to severe acute pain following bunionectomy surgery for a five-day period incorporating tramadol as an active control. The bunionectomy Phase III trial ultimately enrolled 325 patients at five sites in the U.S. The design and analysis of the study compared 200 mg and 400 mg t.i.d. of bicifadine to placebo with 100 mg t.i.d. of tramadol as an active control. Statistically significant increases in analgesia were measured as early as 30 minutes after administration and these effects were sustained for the balance of the eight-hour measurement period. The maximal efficacy of bicifadine was statistically indistinguishable from tramadol. While both bicifadine and tramadol were safe and relatively well-tolerated without producing any serious adverse events, the high level of “rescue” analgesic medication used in both the placebo and active drug groups confounded an assessment of the analgesic actions of bicifadine or tramadol under repeat dosing conditions, which are an FDA requirement. |
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Depression (top) Depression is a disorder in which the affected person experiences a mental state of sadness, despair, discouragement and hopelessness. Other symptoms may include apathy, withdrawal from social contact, an inability to experience pleasure, changes in appetite and sleep patterns, low energy levels, difficulty concentrating and thoughts of suicide. Neurotransmitters regulate numerous functions in the CNS, 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 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 and duration of action 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 U.S. increased from approximately $424 million in 1987, the year prior to the introduction of Prozac, to approximately $13.7 billion in 2004. Despite this widespread commercial success, SSRIs suffer from the following limitations:
Both preclinical studies and clinical trials indicate that a drug inhibiting uptake of all three, serotonin, norepinephrine and dopamine, may produce a faster onset of action or provide greater efficacy than traditional antidepressants. We believe that such a ‘broad spectrum’ antidepressant would represent a breakthrough in the treatment of depression. DOV 21,947 and DOV 216,303 (top) For the treatment of depression DOV 21,947 and DOV 216,303 are triple reuptake inhibitors, or TRIs, affecting the neurotransmitters serotonin, norepinephrine and dopamine. In preclinical studies, DOV 21,947 and DOV 216,303 were shown to inhibit the uptake of all three neurotransmitters. In animal models highly predictive of antidepressant action, DOV 21,947 and DOV 216,303 were more potent than Tofranil®, an SNRI, and the SSRIs Prozac and Celexa. Because of their ability to inhibit the uptake of all three neurotransmitters implicated in depression, we believe DOV 21,947 and DOV 216,303 may be more effective and have a more rapid onset than other antidepressants. We have completed several Phase I studies of DOV 21,947 and intend to initiate a Phase II clinical trial in the third quarter of 2006. Before sublicensing DOV 216,303 to Merck, we completed a Phase II efficacy trial in patients with major depressive disorder. The clinical trial was a randomized, multi-center, double-blind, safety, efficacy and tolerability study comparing DOV 216,303 to citalopram, an SSRI. Patients who completed two weeks of treatment in both the DOV 216,303 and citalopram groups demonstrated reductions from baseline (p<0.0001) in the total HAM-D scores. This study also showed that DOV 216,303 was generally well-tolerated, with no serious adverse events occurring. Merck has licensed the rights to DOV 216,303 for depression, anxiety and addiction. We are currently evaluating DOV 216,303 in preclinical models to determine additional indications, outside of the Merck indications, to pursue in clinical development. Alcohol Abuse and Alcoholism (top) Alcoholism, also known as alcohol dependence, is a disease with symptoms including:
DOV 102,677 (top) For the treatment of alcohol abuse & alcoholism DOV 102,677 is a TRI with preferential action on the dopamine transporter protein and is related to DOV 21,947 and DOV 216,303. In a Phase Ia clinical trial, DOV 102,677 was shown to be safe and well-tolerated at doses ≤ 150 mg. Results of this Phase Ia trial and results from an animal model of alcohol abuse have led us to identify DOV 102,677 as a development candidate to treat alcohol abuse and alcoholism rather than depression. We intend to initiate a Phase Ib repeat-dose clinical trial in normal volunteers for DOV 102,677 in the alcohol abuse indication in 2007. |
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Cardiovascular Disorders
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Angina (top) Chronic stable angina, or angina pectoris, refers to recurring severe constricting pain in the chest due to inadequate blood supply to the heart caused by heart disease. Angina attacks are more likely to occur during the morning and afternoon hours. Likewise, hypertension is greater in the morning hours. According to the 2002 practice guidelines update for the management of patients with chronic stable angina, published by the American College of Cardiology/American Heart Association/American College of Physicians-American Society of Internal Medicine, the number of patients in the U.S. with stable angina was estimated at 16.5 million. According to Decision Resources, high blood pressure or hypertension was estimated to affect more than 50 million people in the U.S. Diltiazem belongs to a well-known class of drugs called calcium channel blockers. Calcium channel blockers remain a standard of care in the treatment of chronic stable angina and hypertension and continue to be highly endorsed by the medical community. Although comparative studies have demonstrated equivalent anti-angina effects for many marketed calcium channel blockers, a lower incidence of side effects with diltiazem was often reported in these studies. According to IMS figures for 2004, sales of diltiazem products in the U.S. totaled $799 million. In an effort to provide both therapeutic blood levels of diltiazem for longer periods of time and improved patient compliance, several slow or extended release preparations of diltiazem have been developed for the treatment of hypertension and chronic stable angina. However, these commercially available, once-daily, extended release formulations produce only a partial reduction of chronic stable angina. According to published studies, currently marketed diltiazem products such as Tiazac®, Cardizem® and Dilacor XR® only reduce the number of angina attacks by approximately 50-60 percent when given at FDA-approved therapeutic doses. We believe incomplete reduction in angina demonstrated by current treatments may be the result of inadequate blood levels of the drug in the morning hours, when approximately half of all angina attacks occur. Experts in chronic stable angina have confirmed their dissatisfaction with the ability of current extended release products to adequately treat many of their patients on a once-a-day basis. DOV Diltiazem (top) For the treatment of angina & hypertension DOV Diltiazem, our proprietary formulation of diltiazem, is our product candidate for the treatment of angina and hypertension. DOV diltiazem combines an immediate release component with a controlled release component in order to provide prompt and improved blood levels throughout the day compared to currently marketed diltiazem products. We believe that DOV diltiazem will reduce morning angina attacks to a significantly greater extent than commercially available products because of its combination of immediate and extended release components. Data from three Phase I trials indicate that our patented formulation produces clinically relevant blood levels within 30 minutes of administration and results in higher blood levels in the morning than Tiazac. In 2004, we reached agreement with the FDA’s Cardio-Renal Division on the scope and design of the clinical trials required for submission of an NDA for DOV diltiazem. The FDA agreed that no additional preclinical or toxicology studies would be required for the NDA submission. We are currently evaluating strategic relationships to advance DOV diltiazem into Phase III clinical development and commercialization while continuing to focus primarily on our CNS programs. We intend that further clinical development of DOV diltiazem be conducted by a licensee of this product, assuming we are able to secure attractive license terms. |
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Preclinical Development (top) Our discovery program remains focused on GABAA receptor modulators and reuptake inhibitors for the treatment of CNS disorders. Our internal discovery effort with GABAA receptor modulators has yielded a series of compounds we are currently evaluating. These new chemical entities, currently in the lead optimization phase, are significantly more potent than ocinaplon, our previous anti-anxiety product candidate, and we have prioritized our preclinical pipeline and 2006 activities accordingly. These compounds appear to function as partial positive allosteric modulators at specific GABAA receptor subtypes that may be involved in the treatment of various anxiety disorders, including generalized anxiety disorder, or GAD, and panic. Our preclinical research and discovery activities and program also includes our work to identify second generation bicifadine compounds. |
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