About TO-2061

Transcept is developing TO-2061, a low dose form of ondansetron, as an adjunctive therapy in patients with obsessive compulsive disorder (OCD) who have not adequately responded to approved first-line therapy.  OCD affects 1 to 2 percent of the United States adult population and can significantly impair the lives of patients and their families. Approximately 50 percent of patients do not respond adequately to standard first-line treatment with approved OCD medications, including the selective serotonin re-uptake inhibitors (SSRIs) and the tricyclic agent, clomipramine. There is no FDA approved augmentation therapy for these treatment resistant patients.

Ondansetron, a serotonin subtype 3 (5-HT₃) receptor antagonist, first received FDA approval in 1991 and has an established history of clinical use as a safe and effective treatment for nausea and vomiting induced by chemotherapy, radiation therapy and surgery. A typical anti-emetic daily dose of ondansetron is 16 mg to 24 mg. Transcept is studying ondansetron at reduced total daily doses of 1.0 mg to 1.5 mg in the adjunctive treatment of OCD patients.

TO-2061 is the second Transcept product candidate and, like Intermezzo^®, was internally conceived by the Transcept research and development group.

TO-2061 Phase 2 Study

Transcept is currently conducting a Phase 2, double-blind, placebo-controlled multi-center proof of concept study with TO-2061. Approximately 150 OCD patients will be randomized into three groups to evaluate the safety and efficacy of TO-2061 compared to placebo. Patients with a documented history of at least 6 weeks of inadequate response to their current OCD medication will continue to receive that OCD medication for an additional 6 week run-in phase of the study.  Those patients who fail to respond to this course of therapy will then be eligible to enter the 12 week active treatment phase, during which they will continue to receive their first-line therapy with the addition of ondansetron 0.50 mg twice per day, ondansetron 0.75 mg twice per day or placebo. The primary endpoint of the study is the difference between active and placebo treatment arms as measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS).

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Low Dose Ondansetron Studies

The TO-2061 Phase 2 study design is based in part on data from two single-blind pilot studies conducted by Eric Hollander, MD and Stefano Pallanti, MD.

Pilot Study A: In an open label study of 14 OCD patients who responded poorly to at least 12 weeks of SRI treatment combined with an atypical antipsychotic, 9 nine patients, or 64.3 percent, responded with a 25 percent or greater reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score, and a Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2 at 12 weeks. The average reduction in YBOCS rated symptoms for the whole group was 23.2 percent. None of the treated patients experienced symptom exacerbation or significant adverse effects. (S. Pallanti, S. Bernardi, S. Antonini, N. Singh, E. Hollander: Ondansetron augmentation in Treatment-Resistant Obsessive-Compulsive Disorder, CNS Drugs 2009.)

Pilot Study B: In an open label study of 21 OCD patients who responded poorly to at least 12 weeks of SSRI treatment, the average decrease in the Yale Brown Obsessive Compulsive Scale (YBOCS) was 26.3 percent. Twelve of these patients, or 57 percent, responded with a 25 percent or greater reduction in YBOCS, and a mean Clinical Global Impressions-Improvement (CGI-I) score of 1.2 at 12 weeks. The average YBOCS score in this responder group improved 44 percent from baseline at 12 weeks. In the non-responder group, those patients whose YBOCS reduction was less than 25 percent, the average YBOCS score improved 2.9 percent from baseline at 12 weeks. Four weeks after discontinuation of low dose ondansetron treatment, the average YBOCS score of the responder group worsened 38.3 percent from the end of treatment score. None of the treated patients experienced symptom exacerbation or significant adverse effects. (S. Pallanti, S. Bernardi, E. Hollander: Ondansetron augmentation in Treatment-Resistant OCD (TR-OCD): Hot topics and poster presentation, American College of Neuropsychopharmacology 49th Annual Conference, December 2010.)

About obsessive compulsive disorder (OCD)

Obsessive compulsive disorder (OCD) is characterized by a pattern of unwanted and intrusive thoughts that cause distress and consequent repetitive behaviors aimed at reducing this distress. OCD affects approximately 1 to 2 percent of the U.S. adult population and can significantly impair the lives of patients and their families.⁽¹⁾⁽²⁾ Greater social impairment has been reported in patients with OCD as compared to those with social anxiety or panic disorder.⁽³⁾ It is believed that the overall degree of impairment caused by OCD is comparable to that experienced by patients who suffer with schizophrenia.⁽⁴⁾⁽⁵⁾

SSRIs, including Prozac^® (fluoxetine), Luvox^® (fluvoxamine), Paxil^® (paroxetine), and Zoloft^® (sertraline), and the tricyclic agent, clomipramine, are the only approved medications for OCD. While these medications are used as first-line treatment for OCD, 40 percent to 60 percent of OCD patients do not respond adequately⁽⁶⁾, and there is no FDA-approved adjunctive therapy for this treatment resistant group of patients. Atypical antipsychotic drugs are often used off label to augment approved OCD medications when patients are treatment resistant. However, atypical antipsychotic drugs are associated with significant side effects, including weight gain and metabolic disorder, and approximately two-thirds of OCD patients who do not adequately respond to the approved OCD medications also do not respond to this combination therapy.⁽⁷⁾ Atypical antipsychotics have not been approved by the FDA for the treatment of OCD patients or OCD patients.

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(2) U.S. Department of Health and Human Services. Mental Health: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, National Institutes of Health, National Institute of Mental Health, 1999.

(3) Lochner C, et al. Quality of life in anxiety disorders: A comparison of obsessive-compulsive disorder, social anxiety disorder, and panic disorder. Psychopathology (2003) 3, 255-262.

(4) Bobes J, et al. Quality of life and disability in patients with obsessive-compulsive disorder. European Psychiatry (2001) 16, 239-245.

(5) Bystritsky A, et al. Social functioning and quality of life comparisons between obsessive-compulsive and schizophrenic disorders. Depression and Anxiety (2001) 14, 214-218.

(6) Hewlett WA, et al. Pilot trial of ondansetron in the treatment of 8 patients with obsessive-compulsive disorder. J Clin Psychiatry (2003) 64, 1025-1030.

(7) Bloch MH, et al. Treatment refractory obsessive compulsive disorder. Molecular Psychiatry (2006) 11, 622-632.