LEXINGTON, Mass., June 12 /PRNewswire-FirstCall/ -- Indevus Pharmaceuticals, Inc. today announced that results from the Company’s Phase II EXPRESS trial for pagoclone in persistent developmental stuttering will be presented today at the 47th annual meeting of the New Clinical Drug Evaluation Unit (NCDEU), sponsored by National Institute for Mental Health (NIMH) and being held in Boca Raton, Florida. In addition, the presentation will include data from the first three months of open label treatment.
“The progress of the ongoing Phase II open-label phase has been extremely encouraging,” stated Glenn L. Cooper, M.D., chairman and chief executive officer of Indevus. “Our investigators are reporting significant benefit for the vast majority of patients continuing in the open label phase and for several patients, these benefits have been life-changing.”
“The results from the open-label extension study reveal that pagoclone is a promising medication for the long-term treatment of stuttering,” stated Gerald A. Maguire, M.D., associate professor, department of psychiatry, University of California, Irvine School of Medicine. “As a researcher and a person who stutters, I am excited about the results. Although there is no cure for stuttering, this study suggests that pagoclone holds significant promise as a well-tolerated, effective pharmacologic treatment for stuttering and further studies are indicated.”
The open label data demonstrated an improvement in nearly all efficacy measures compared to baseline that was at least double the magnitude seen in the initial 8 weeks of double-blind treatment. During the 8-week, double-blind portion of the study, patients who were randomized to placebo experienced a mean reduction in the percentage of syllables stuttered of 5%. After three months in the open label portion of the study, these same patients experienced a 31% mean reduction. These open label gains lagged slightly the gains made by patients originally randomized to 8 weeks of active pagoclone (5 months total exposure). For those patients randomized to pagoclone in the double- blind phase, the mean reduction in percent syllables stuttered was 18%, while in the open label phase, the mean reduction was 40%.
Similarly, data for the Clinician’s Global Impression of Improvement (CGI- I) showed considerable gains during the three months of open label treatment. For patients receiving placebo during the double blind phase, 36% were rated as improved, while following three months of open label treatment, 80% were rated as improved. For patients receiving active pagoclone during the double blind phase, 55% had been rated as improved, and following three additional months of open label treatment with pagoclone, 90% were rated as improved. These results indicate that, while the beneficial effects of pagoclone were evident within the 8-week double-blind phase, the magnitude of benefit continued to grow for at least three months. Pagoclone has continued to demonstrate a very favorable safety profile during the open label phase. These results have been submitted for publication to a leading journal in this field.
Additionally, approximately half the patients who participated in the double-blind phase had a high level of social anxiety symptoms pre-treatment, as measured using the Liebowitz Social Anxiety Scale (LSAS). In this high- severity subgroup, pagoclone demonstrated statistically significant improvements in the LSAS Total scale compared with placebo. Both groups, those receiving active pagoclone as well as those receiving placebo, demonstrated continued improvement, achieving over a 20 point mean decrease over the five month period.
Study Design
The Phase II study, known as the EXPRESS trial, was an 8-week, placebo controlled, double-blind, multi-center trial with an open label extension. There were a total of 132 patients randomized in the trial. Eighty-eight patients received escalating doses of pagoclone from 0.3 mg to 0.6 mg per day. Forty-four patients received placebo. Seventy-nine percent of the patient population was male, which is reflective of the gender distribution of this disorder. Although open label treatment is not blinded, patients and investigators remained blinded to the original treatment allocation during the 8-week double-blind phase.
More than 70% of the 119 patients who entered the open label phase of the EXPRESS trial were included in the three month open label data being presented at NCDEU.
Study Results
The primary endpoints evaluated in the double-blind, phase of the study were the Frequency and Duration Subscale of the Stuttering Severity Instrument Version 3 (SSI-3), the Stuttering Severity Scale (SEV) and the Subjective Screening of Stuttering (SSS) Severity Subscore. Given that this was an exploratory study, pre-specified analyses utilized 1-tailed tests of significance.
The SSI-3 is a validated measure of stuttering. During study visits at week 4 and week 8, patients were videotaped while engaged in both a conversational and reading task. The videotapes were analyzed and scored at a central laboratory. Raters were blinded with regard to treatment and visit. The frequency and duration subscales were calculated by measuring the proportion of syllables stuttered compared to syllables spoken and the length of time of each stuttering block or event. The variability of stuttering naturally tends to wax and wane over time. Accordingly, two data points were collected prior to treatment and two data points were collected while on treatment at week 4 and week 8 to determine the on-treatment effect of pagoclone. The on-treatment effect of pagoclone was shown to produce a statistically significant reduction in the frequency and duration of stuttering as measured by the SSI-3 scale when compared to placebo (p=.02). While receiving 8 weeks of placebo, patients had experienced a mean reduction of approximately 5% in the percentage of syllables stuttered, however after three months of open label treatment, patients achieved a reduction of 31%. These open label gains lagged slightly the gains made by patients originally randomized to 8 weeks of active pagoclone (5 months total exposure), who had, during the double blind phase, experienced a mean reduction of 18% of syllables stuttered and then went on to achieve a reduction of 40% of syllables stuttered after three months of the open label extension.
The SEV, measured at week 2, week 4 and week 8, is a validated measure of stuttering. The SEV is a 9-point, clinician rated severity scale anchored by “no stuttering” and “extremely severe stuttering.” The on-treatment effect of patients receiving pagoclone demonstrated a numerically superior rating versus patients treated with placebo (p=.18).
The SSS Severity Subscore, measured at week 2, week 4 and week 8, is a validated, patient-rated assessment of stuttering that takes into account specific speaking situations that have taken place over the prior week. Pagoclone produced a statistically significant reduction at week 2 (p=.004) and week 4 (p=.05) and a trend for significant improvement at week 8 (p=.08) as compared to placebo.
The secondary endpoints evaluated in the study included the Clinician Global Impression-Improvement (CGI-I), the Liebowitz Social Anxiety Scale (LSAS) and the Speech Naturalness Scale (SNS).
The CGI-I, measured at week 2, week 4 and week 8, is a 7-point, validated and widely accepted clinician-rated measure of improvement as compared to baseline, considering all sources of available clinical information about the patient. For analysis of the improvement in the severity of stuttering, patients were categorized as having either “improved” versus “no change or worsened.” Pagoclone produced numerically superior improvement at week 2 (p=.20) and statistically significant improvement at week 4 (p=.007) and at week 8 (p=.02) as compared to placebo. At week 8, 55% of pagoclone treated patients were improved compared to 36% of placebo treated patients. Open label data showed considerable gains after three months of open label treatment. For patients receiving placebo during the double blind phase, 36% were rated as improved, but following 3 months of open label treatment, 80% were rated as improved. For patients receiving active pagoclone during the double blind phase, 55% had been rated as improved, and following 3 additional months of open label treatment, 90% were rated as improved. These results indicate that, while the beneficial effects of pagoclone were evident within the 8-week double-blind phase, the magnitude of benefit continued to grow for at least three months.
The LSAS, measured at week 4 and week 8, is a validated measure of social anxiety symptoms. Stuttering is often co-morbid with symptoms of social anxiety which can be a disabling consequence of stuttering. Although patients with primary anxiety disorders were excluded from participating in the trial, pagoclone produced a trend for significant improvement in social anxiety symptoms (total LSAS score) compared to placebo at week 4 (p=.09) and week 8 (p=.07). On a subscale comprised of the elements of the LSAS that evaluate anxiety-provoking speaking situations, pagoclone produced statistically significant improvement at both week 4 (p=.02) and week 8 (p=.02). Approximately half the patients who participated in the double-blind phase had a high level of social anxiety symptoms pre-treatment, as measured using the LSAS. Patients treated with pagoclone demonstrated statistically significant improvements in the LSAS Total scale compared with placebo. During the open label extension, both groups, those receiving active pagoclone as well as those receiving placebo, demonstrated continued improvement, achieving approximately a 20 point mean decrease over the five month period.
Pagoclone was shown to be safe and well-tolerated. There were no serious adverse events associated with pagoclone. The most commonly reported side effects associated with pagoclone were headache (12.5% for pagoclone and 6.8% for placebo) and fatigue (8% for pagoclone and 0% for placebo). As with all prior trials for pagoclone, reports of somnolence and sedation were similar between pagoclone and placebo. Additionally, pagoclone exerted its clinical effect on patients without disrupting the naturalness of their speech as assessed by the SNS, a validated 9-point scale.
Pagoclone has continued to demonstrate a very favorable safety profile during the open label phase.
About Stuttering
Nearly 3 million Americans, or as much as 1% of the population, are afflicted with persistent stuttering, with approximately 4 times as many males being affected by the condition as females. Stuttering is a DSM-IV-TR Axis I disorder and is characterized by symptoms in which the flow of speech is disrupted by prolongations, repetitions, and blocks of sounds, syllables, words or phrases. The exact cause of stuttering is unknown; however, emerging evidence has shown that this disorder is associated with abnormalities in brain areas related to speech motor control. Stuttering most often begins in early childhood. It often persists into adulthood and this form is classified as persistent developmental stuttering. Given the importance of communication in daily life, stuttering impairs an individual’s academic, social and occupational functioning. No medication is FDA approved for stuttering and the most commonly utilized treatment is speech therapy.
About pagoclone
Pagoclone is a novel, non-benzodiazepine, GABA-A selective receptor modulator. It is part of a new chemical class of agents and lacks many of the common benzodiazepine side effects such as sedation and withdrawal. The precise mechanism of action is unknown, however, GABA is believed to be an important neurotransmitter in the brain that may be disrupted in people who stutter. Pagoclone enhances the activity in GABA circuits in the brain and thus may help restore more normal function in speech areas of the brain.
About Indevus
Indevus Pharmaceuticals, Inc. is a specialty pharmaceutical company engaged in the acquisition, development and commercialization of products to treat conditions in urology and endocrinology. The Company’s approved products include SANCTURA(R) for overactive bladder, VANTAS(R) for advanced prostate cancer, and DELATESTRYL(R) to treat male hypogonadism, all of which are currently marketed, as well as SUPPRELIN(R) LA, which was recently approved for central precocious puberty. The Indevus development pipeline contains multiple compounds within the Company’s core therapeutic areas in addition to several partnered or partnerable programs. The most advanced compounds in development include SANCTURA XR(TM), the once-daily formulation of SANCTURA, VALSTAR(R) for bladder cancer, NEBIDO(R) for male hypogonadism, PRO 2000 for the prevention of infection by HIV and other sexually-transmitted pathogens, and pagoclone for stuttering.
Forward-Looking Statements
Except for the descriptions of historical facts contained herein, this press release contains forward-looking statements that involve risks and uncertainties that could cause the Company’s actual results and financial condition to differ materially from those anticipated by the forward-looking statements. These risks and uncertainties are set forth in the Company’s filings under the Securities Act of 1933 and the Securities Exchange Act of 1934 under “Risk Factors” and elsewhere, and include, but are not limited to: dependence on the success of SANCTURA(R), SANCTURA XR(TM), NEBIDO(R) and VANTAS(R); the early state of products under development; uncertainties relating to clinical trials, regulatory approval and commercialization of our products, particularly SANCTURA XR, NEBIDO, VALSTAR(R) and SUPPRELIN(R)-LA; risks associated with contractual agreements, particularly for the manufacture and co-promotion of SANCTURA and SANCTURA XR and the manufacture of NEBIDO, VANTAS and VALSTAR; dependence on third parties for supplies, particularly for histrelin, manufacturing, marketing, and clinical trials; competition; need for additional funds and corporate partners, including for the development of our products; failure to acquire and develop additional product candidates; changes in reimbursement policies and/or rates for SANCTURA, VANTAS, DELATESTRYL and any future products; history of operating losses and expectation of future losses; product liability and insurance uncertainties; risks relating to the Redux-related litigation; the risk that the businesses of Indevus and Valera Pharmaceuticals, Inc. will not be integrated successfully during the period following the related merger; the risk that the cost savings and any other synergies from the merger may not be fully realized or may take longer to realize than expected; market acceptance for the merger and approved products; risks of regulatory review and clinical trials; disruption from the transaction making it more difficult to maintain relationships with customers, employees or suppliers; competition and its effect on pricing, spending, third-party relationships and revenues; reliance on intellectual property and having limited patents and proprietary rights; dependence on market exclusivity, valuation of our Common Stock; risks related to repayment of debts; risks related to increased leverage; general worldwide economic conditions and related uncertainties; the effect of changes in governmental regulations and other risks. Indevus undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Contact: Michael W. Rogers Brooke D. Wagner Executive Vice President and CFO VP, Corp. Communications (781) 861-8444 (781) 402-3410
Indevus Pharmaceuticals, Inc.
CONTACT: Michael W. Rogers, Executive Vice President and CFO,+1-781-861-8444, or Brooke D. Wagner, VP, Corp. Communications,+1-781-402-3410, both of Indevus Pharmaceuticals
Web site: http://www.indevus.com/
