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Bicifadine
Market Opportunity
Neuropathic pain is a chronic condition resulting from damage to peripheral nerves. According to Datamonitor, there are over 15 million people suffering from neuropathic pain in the United States alone. With limited treatment options available, neuropathic pain represents a significant unmet medical need. According to Datamonitor, the global market for neuropathic pain drugs is expected to grow from $3.6 billion in 2006 to over $7 billion by 2016.
Diabetic neuropathic pain, which manifests itself primarily in the feet, can often be debilitating thus preventing patients from carrying out their normal day-to-day activities. In the US, it is estimated that approximately 4.5 million patients with diabetes suffer from diabetic neuropathic pain. Diabetic neuropathic pain is the largest segment in the rapidly growing market for neuropathic pain drugs. Only two oral drugs have been approved to date by the FDA for the treatment of diabetic neuropathic pain (Eli Lilly's Cymbalta®, an SNRI, and Pfizer's Lyrica®); however, the response rates to these drugs are limited. Consequently, millions of patients remain without adequate treatment options and seek new drugs that could provide better relief for their chronic pain.
Scientific Background
Bicifadine is a serotonin and norepinephrine reuptake inhibitor. Serotonin and Norepinephrine Reuptake Inhibitors (SNRI's) are drugs that increase the levels of serotonin and norepinephrine in the brain, thus blocking pain signals. SNRI is a proven drug class in diabetic neuropathic pain as well as Major Depressive Disorder. One SNRI (Eli Lilly's Cymbalta®) is already approved for the treatment of diabetic neuropathic pain, while a second SNRI (Wyeth's Effexor®) has demonstrated efficacy in treatment of diabetic neuropathic pain in large, randomized and placebo-controlled studies. Both Cymbalta® and Effexor® are also approved for depression. A third SNRI (Cypress' Milnacipran®) recently demonstrated efficacy in a Phase 3 trial in a related neuropathic pain indication (fibromyalgia), providing further evidence of the efficacy of the SNRI class in neuropathic pain.
Activity on norepinephrine reuptake is thought to be necessary for anti-depressants to be effective in neuropathic pain. Compared to the currently approved SNRI's, Bicifadine has a unique ratio of serotonin versus norepinephrine reuptake inhibition, which is weighted toward norepinephrine reuptake inhibition, providing a strong scientific rationale for using Bicifadine for the treatment neuropathic pain indications.
Clinical Data
Four Phase 1 clinical trials and 14 Phase 2 clinical trials involving more than 1,000 patients have been conducted with an immediate release, or IR, formulation of Bicifadine for the treatment of acute pain. In five exploratory double-blind, placebo-controlled Phase 2 clinical trials of the IR formulation, 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, eight Phase 1 clinical trials using the sustained release, or SR, formulation of Bicifadine have been conducted. SR is a formulation that generally permits less frequent daily dosing and improves tolerability. We intend to use the SR formulation in future clinical development and for commercial use of Bicifadine.
In two additional larger (n=750 and n=540) single-dose, double-blind, placebo-controlled clinical trials with Bicifadine in the treatment of moderate to severe post-surgical acute dental pain, Bicifadine produced a highly statistically significant, dose-related reduction in pain compared to placebo, and which was comparable to a positive control arm (codeine or Tramadol). Both trials demonstrated Bicifadine to be safe and generally well-tolerated without producing any serious adverse events.
In a Phase 3 double-blind, placebo-controlled, clinical trial (n=325) with Bicifadine in the treatment of moderate to severe acute pain following bunionectomy surgery, 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. In this study, Bicifadine was safe and generally well-tolerated. The complete assessment of the analgesic action of Bicifadine under repeat dosing conditions could not be fully elucidated due to the high level of "rescue" analgesic medication used in both the placebo and active drug groups.
Due to the highly competitive nature of the market for acute pain drugs, and the FDA requirement to complete two repeat-dosing clinical trials in two different acute pain indications, no further studies in acute pain are planned.
Bicifadine has been further evaluated in three Phase 3 trials in chronic lower back pain, or CLBP. The primary efficacy endpoint in these trials was the change in pain severity rating score between baseline and the end of dosing. In these trials, Bicifadine was safe and generally well tolerated, but did not show a statistically significant effect relative to placebo on the primary endpoint of the study at any of the doses tested.
We believe that the failure of Bicifadine in the CLBP trials was a result of the inherent heterogeneity of the studied patient population (i.e. the varying causes of CLBP pain), uncontrolled physical activities in what is largely an activity-dependent pain indication, and a high placebo response.
We believe that by re-directing the development of Bicifadine away from the novel indications in acute and chronic pain toward a proven area of efficacy of SNRI's in the treatment of neuropathic pain, Bicifadine could be successfully developed for neuropathic pain, possibly offering a differentiated efficacy and safety profile based on the drug's emphasis on norepinephrine reuptake inhibition.
Development Status
The Phase 2b trial that was initiated in September 2007 is aimed at demonstrating the efficacy of Bicifadine in diabetic neuropathic pain, using a study design that is similar to the successful registration trials of Cymbalta®, a member of the SNRI class that is approved for this indication, and other approved agents for neuropathic pain.
The Phase 2b study is a randomized, double-blind, placebo-controlled study comparing 200mg 3x/day (tid) and 400mg 3x/day (tid) of Bicifadine versus placebo, with a 1:1:1 randomization between the three arms, in patients with diabetic neuropathic pain. The Phase 2b study is designed to enroll approximately 336 patients. Approximately 45 clinical centers in the United States, Europe, Israel and India are participating in the study. Following randomization, all patients enter a two week titration period to allow them to gradually escalate up to their target treatment dose. This is then followed by a twelve week steady-state treatment period at the target treatment dose. The primary endpoint of the study is to compare the efficacy of each of the two active doses of Bicifadine (200mg tid and 400mg tid) versus placebo in reduction of pain associated with diabetic neuropathy, at baseline (at the time of randomization) versus week 14 (week twelve of the steady-state phase). Pain will be measured based on a 24-hour pain rating using the eleven point Pain Intensity Numeric Rating Scale (formerly referred to as the LIKERT scale).
In addition, in January 2008, we initiated an open-label variable-dose trial assessing the safety of Bicifadine in patients with diabetic neuropathic pain (the "open label study"). Eligible patients for the open label study will have completed all study visits of the Phase 2b clinical trial. Subjects who satisfy all inclusion and exclusion criteria will be titrated to a dosage of 600 mg/day (200 mg tid). Depending upon efficacy and tolerability the dosage can be progressively increased to 1200 mg/day (400 mg tid). The dosage can be altered throughout the trial but may not go below 600 mg/day (200 tid) or above 1200 mg/day (400 tid). The open label study is designed to enroll approximately 240 patients.
DOS Program
The Diversity Oriented Synthesis, or DOS, program, is focused on the development of novel pre-clinical hepatitis C small molecule inhibitors. Compounds developed to date inhibit HCV replication in a pre-clinical cell-based assay with potencies comparable to clinical stage drugs. In March 2008, we signed an agreement to out-license our DOS program to Presidio. Under the terms of the license agreement, Presidio becomes responsible for all further development and commercialization activities and costs relating to the DOS program. In accordance with the terms of the license agreement, we received a $4 million, non-refundable, upfront payment in cash from Presidio and will receive up to an additional $104 million upon reaching certain development and commercialization milestones. In addition, we will receive a royalty on direct product sales by Presidio, and a percentage of Presidio's income if the DOS program is sublicensed by Presidio to a third party.
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